Treatment and Management of Muscular Dystrophies

Diana M. Escolar, MD, Peter O'Carroll, MD, and Robert Leshner, MD

Treatment and Management of Muscular Dystrophies

Muscular dystrophies have long been recognized as inherited disorders, characterized by progressive skeletal muscle degeneration and weakness. These diseases are known to have autosomal dominant, recessive, or X-linked inheritance. Clinical observations initially led to classification into six groups: Duchenne-like, Emery-Dreifuss type, limb-girdle type, facioscapulohumeral peroneal type, distal myopathies, and oculopharyngeal type.1 The expanding genetic and molecular understanding of the muscular dystrophies has further complicated their classification. An updated classification system for these disorders is shown in Table 19-1. The underlying molecular defects responsible for these disorders are found throughout the cellular structure, including extracellular matrix structural proteins (laminin-2, collagen type VI) and glycosylation enzymes (fukutin-related protein [FKRP], protein-Omannosyl transferases 1 and 2 [POMT1 and POMT2], protein-O mannose b1,2-N-acetylglucosaminyltransferase 1 [POMGNT1]), transmembrane- and sarcolemma-associated proteins (dystrophin, sarcoglycans, dystroglycan, caveolin-3, b1- and a7-integrins, dysferlin), cytoplasmatic proteases and ligases (calpain-3, tripartite motif-containing 32 [TRIM32]), cytoplasmic proteins associated with organelles and sarcomeres (titin, myotilin, fukutin, telethonin), and nuclear membrane proteins (lamin, emerin). These diseases have provided a window to better understanding of sarcolemmal organization and the underlying muscle biology responsible for the structure and maintenance of normal muscle cell function. The relationships between these proteins are complex; the function of each of the defective proteins, including the most investigated one, dystrophin, is not entirely known. Structural, enzymatic, and signaling dysfunctions provide the basis for the pathophysiology that has been associated with these disorders. Figure 19-1 shows a current depiction of the muscle membrane as well as other areas of the muscle fiber associated with muscular dystrophies.

Dystrophinopathies Dystrophinopathies are a group of dystrophies resulting from mutations in the dystrophin (DMD) gene, located on the short arm of the X chromosome in the Xp21 region.2 Duchenne muscular dystrophy (DMD) is the most common dystrophinopathy and represents a complete absence of the subsarcolemmal protein dystrophin. Becker muscular dystrophy (BMD), which is rarer, involves a decrease in the

19

quantity or quality of the dystrophin protein. This gives rise to a milder disease with variable severity and time of clinical onset. Duchenne and Becker Muscular Dystrophies The clinical and pathologic features of DMD were first described in 1851 by Edward Meryon, an English physician, in a communication about eight boys in three British families who had the disease. Several years later, in 1868, the French neurologist GuillaumeBenjamin Duchenne described the same syndrome in detail, and it ultimately would bear his name. Several other meticulous descriptions of the disease can be found in the early literature. Molecular Pathogenesis The DMD gene consists of 86 exons (including seven promoters linked to unique first exons), which make up only 0.6% of the gene. The gene, which spans a genetic distance of more than 2.5 million base pairs,3 is the largest isolated human gene. More than 90% of boys with DMD have an absence of dystrophin corresponding to an “out-of-frame” mutation that disrupts normal dystrophin transcription.4 These mutations cause a premature stop codon and early termination of mRNA transcription. As a result, an unstable RNA is produced that undergoes rapid decay, leading to the production of nearly undetectable concentrations of truncated protein. If the mutation is one that does not stop transcription, an “in-frame” deletion, the BMD phenotype occurs, with abnormal dystrophin protein.5 This reading frame hypothesis holds for more than 90% of cases and is commonly used both to confirm diagnosis of dystrophinopathies and to differentiate between DMD and BMD. Exceptions occur in approximately 10% of patients. Out-of frame deletions affecting exons 3-7, 5-7, 3-6, or downstream at exons 51, 49-50, 47-52, 44, or 45 can result in a milder BMD phenotype. The most common underlying explanation for the presence of at least some dystrophin in these patients is a process called exon skipping, which occurs via alternative splicing.6,7 In these BMD patients the carboxy-terminus is always preserved.8 The involved exons are generally thought to encode noncritical areas of the protein so that when they are skipped, a shortened but still functional dystrophin protein is produced. Exon skipping is also the underlying mechanism for the revertant fibers (a few scattered muscle fibers showing dystrophin staining in muscle biopsies) seen in approximately 50% of DMD boys.9 The limited expression of dystrophin results in a 343

344 Treatment and Management of Specific Neuromuscular Disorders Table 19-1 Pathophysiological Classification of Muscular Dystrophies

Disease

Gene Locus

Gene Product

Mode of Inheritance

Limb-girdle Muscular Dystrophy (LGMD) Caused by Sarcolemma or Cytosolic Protein Defects

Duchenne/Becker MD

Xp21

Dystrophin

XR

LGMD 1A

5q22

Myotilin

AD

LGMD 1B

1q21.2

Lamin A/C

AD

LGMD 1C

3p25

Caveolin 3

AD

LGMD 1D

7q

?

AD

LGMD 1E

6q23

?

AD

LGMD 1F

7q32

?

AD

LGMD 1G

4q21

?

AD

LGMD 1H

3p23

?

AD

LGMD 2A

15q15

Calpain 3

AR

LGMD 2B/Myoshi myopathy

2p13.1

Dysferlin

AR

LGMD 2C

13q12

Gamma-sarcoglycan

AR

LGMD 2D

17q21

Alpha-sarcoglycan

AR

LGMD 2E

4q12

Beta-sarcoglycan

AR

LGMD 2F

5q33

Delta-sarcoglycan

AR

LGMD 2G

17q11.2

Telethonin (TCAP)

AR

LGMD 2H

9q31-q33

Tripartite motif-containing 32 (TRIM32)

AR

LGMD 2I

13q13.3

Fukutin-related protein (FKRP)

AR

LGMD 2J/Tibial muscular dystrophy

2q31

Titin

AR/AD

LGMD 2K

9q34.1

Protein-O-mannosyltranseferase (POMT1)

AR

LGMD 2L

11p14.3

ANO5

AR

LGMD 2M

9q31

Fukutin

AR

LGMD 2N

14q24

POMT2

AR

Congenital Muscular Dystrophy (CMD) Secondary to Glycosylation Disorder

Fukuyama MD (syndromic)

9q31

Fukutin

AR

Muscle-eye-brain disease (syndromic)

1p34.1

Protein O-linked mannose b1,2-Nacetylglucosaminyltransferase (POMGnT1)

AR

Walker-Warburg syndrome (syndromic)

9q34.1

Protein-O-mannosyltranseferase (POMT1)

AR

MDC 1A (merosin-negative CMD)

6q22-23

Laminin-a2 (merosin)

MDC 1B (merosin-positive CMD)

1q42

?

AR

MDC 1C

19q13.3

Fukutin-related protein (FKRP)

AR

MDC 1D

22q12.3-q13.1

LARGE

AR

CMD with early rigid spine (RSS)

1p36

Selenoprotein N-1

AR

CMD with ITGA7 mutations

12q

Integrin a7

AR

Ullrich syndrome/Bethlem myopathy

21q22.3 (A1, A2) 2q37 (A3)

Collagen VI a1, a2, and a3

AD

Emerin

XR

Other Congenital Muscular Dystrophies

Muscular Dystrophies Secondary to Nuclear Envelope Defects

Emery-Dreifuss MD X1

Xq28

Emery-Dreifuss MD X2

q21.2

Lamin A/C

AD

Emery-Dreifuss MD X3

1q21.2

Lamin A/C

R

Emery-Dreifuss MD X4

6q25

Synaptic nuclear envelope protein 1 (SYNE1; Nesprin-1)

AD

Emery-Dreifuss MD X5

14q23

SYNE2

AD

Emery-Dreifuss MD X6

Xq26

Four-and-a-half-LIM protein 1 (FHL1)

AR/AD

Muscular Dystrophies Secondary to RNA Metabolism Defects

Myotonic dystrophy 1 (DM1)

19q13.3

Myotonic dystrophy-associated protein kinase (DMPK)

AD

Myotonic dystrophy 2 (DM2)

3q21

Zinc finger, nucleic acid binding protein (ZNF9)

AD

Treatment and Management of Muscular Dystrophies

345

Table 19-1 Pathophysiological Classification of Muscular Dystrophies—Cont’d

Disease

Gene Locus

Gene Product

Mode of Inheritance

Other Muscular Dystrophies of Unknown Mechanism

Facioscapulohumeral dystrophy (FSHD)

4q35

FRG-1 (FSH region gene 1)

AD

Oculopharyngeal MD

14q11.2-q13

PABPN1

AD

Also see Table 12-2. AD, autosomal dominant; AR, autosomal recessive; X, X-linked recessive.

Collagen VI Ullrich syndrome Bethlem myopathy

Basal lamina Laminin-2 -2

Sarcoglycan complex LGMD2C-F

ITGA7

Dystroglycan complex

 

Sarcolemma

Syntrophins TRIM LGMD2H



Integrin complex



ε 

Caveolin-3 LGMD1C



  

Dystrophin (DMD)

Dysferlin - LGMD2B

Filamin C

Dystrobrevin

Calpain 3 LGMD2A

Fukutin FCMD LGMD2L

Emerin EDMD

Actin

T-cap & telethonin - LGMD2G

Golgi complex

FKRP LGMD2I MDC1C

Lamin AC AD-EDMD -LGMD1B Myotilin LGMD1A

POMGnT1 MEBD LGMD2M

POMT1 WWS LGMD2K

nNoS Nucleus

1 7

Calpain 3 - LGMD2A

Actinin

Sarcomere

Filamin C

Titin - LGMD2J

Actin

Myosin

Tropomodulin

Tropomyosin

Troponin

Figure 19-1 Different proteins of sarcolemma and other areas of the muscle fiber associated with muscular dystrophy. EDMD, Emery-Dreifuss muscular dystrophy; FCMD, fukuyama congenital muscular dystrophy; FKRP, fukutin-related protein; ITGA7, integrin, alpha7; LGMD, limb-girdle muscular dystrophy; LGMD2M, limb-girdle muscular dystrophy 2M; MEBD, muscle-eye-brain disease; nNOS, neuronal nitric oxide synthase; POMGnT1, protein O-linked mannose b1,2-N-acetylglucosaminyltransferase; POMT, protein O-mannosyltransferase; TRIM, tripartite motif; WWS, Walker-Warburg syndrome.

346 Treatment and Management of Specific Neuromuscular Disorders

slower progression of muscle weakness compared with the usual Duchenne phenotype.2,10–12 This process is therefore an appealing target for therapy in dystrophinopathies, because pharmacologic induction of exon skipping in DMD patients should produce some quantity of dystrophin and may alleviate the severity of the disease (see discussion of Treatment and Management in this chapter). Approximately 60% of cases of Duchenne and Becker muscular dystrophy are the result of deletions.13–17 Deletions can occur almost anywhere in the DMD gene, but two hotspots have been identified. The most commonly mutated region includes exons 4555 with the genomic breakpoint (i.e., the endpoint of where the deletions actually occurs) lying within intron 44. The second region includes exons 2-19 with genomic breakpoints commonly found in introns 2 and 7.18–21 The other 40% of cases result from small mutations (point mutations resulting in frame-shift or nonsense mutations) or duplications. There is a great deal of variability between the size and type of mutations, how they effect transcription, and the clinical phenotype of the disease. The Leiden database (http://www.dmd.nl/) is a useful resource for phenotype/genotype correlation in cases in which genetic testing and phenotype do not appear to be clearly correlated. The incidence of DMD has been estimated at approximately in 3300 male births.22,23 The most common mode of inheritance is

X-linked recessive, but approximately 30% of cases are spontaneous mutations with no demonstrable family history.23–26 Males are primarily affected, but females may manifest symptoms of DMD if they also exhibit skewed X-inactivation, wherein the abnormal X chromosome is expressed in an excessively abnormal proportion.27–30 Pathophysiology Dystrophin Protein The normal DMD gene creates a 14-kb dystrophin mRNA that encodes dystrophin, a 427-kDa protein. Dystrophin localizes to the subsarcolemmal region in skeletal and cardiac muscle and composes 0.002% of total muscle protein.31–33 Dystrophin binds to the cytoskeletal actin and to the cytoplasmic tail of the transmembrane dystrophin-glycoprotein complex (DGC) protein b-dystroglycan, and through this to a-sarcoglycan, thus forming a link from the cytoskeleton to the extracellular matrix (see Fig. 19-1). The dystrophin protein is also found in brain, smooth muscle, and retina. Primary and Secondary (Downstream) Events Muscle cell death (by apoptosis and necrosis) in the muscular dystrophies is conditional on endogenous biochemical mechanisms and reflects a propensity that varies between muscles and changes with age (Fig. 19-2).34 Although dystrophin deficiency is the primary cause

Dystrophin deficiency

Mislocalization of NOS/syntrophin

Membrane instability “leaky membrane” Fibrosis

Stretch activated Ca channels

Circulating bFGF

Dendritic cell activation

Abnormal fibrosis ECM-bound bFGF

bFGF

NOS

Heparin

Proteases Ca influx

Mast cell degranulation

Inflammation Cytokines/TNF-alpha

Ca2

NADH

CsA

ATP ADP

Cr CyD



PTP

Na

PCr

Abnormal intracellular Ca[Ca2]

OxPhos NADH

ATP

Cr

ADP

PCr

m



Sarcoplasmic reticulum

[Ca2]SR ATP SERCA

Muscle energy crisis hyperpol



Ca

RyR

Mi-CK

DHGs



MM-CK

Pyr

[Ca2] m

TCA cycle

Ca DHPR

X

K Glc

Uniporter 

Grouped/muscle necrosis

Na channels AChR, Na channel

Na

Proteases activation

Activation NF-KB

m

inc. Oxidative stress

KCa

[Ca2]



Abnormal Regeneration

Changes in gene expression Increase calpain activity Apotosis and necrosis

Exercise-induced functional ischemia

ADP MM-CK

Inner membrane

Mitochondria

Figure 19-2 Events in the pathogenesis of muscle necrosis in Duchenne muscular dystrophy. ADP, adenosine diphosphate; ATP, adenosine triphosphate; bFGF, basic fibroblast growth factor; DHGs, dehydrogenases; DHPR, dihydropyridine receptor; ECM, extracellular matrix; MM-CK, MM fraction of creatine kinase; NADH, nicotinamide adenosine dinucelotide (reduced); NOS, nitric oxide synthase; SERCA, sarcoplasmic/endoplasmic Ca2þ ATPase; SR, sarcoplasmic reticulum; TCA, tricarboxylic acid cycle; TNF, tumor necrosis factor.

Treatment and Management of Muscular Dystrophies

of DMD, multiple secondary pathways are responsible for the progression of muscle necrosis, the abnormal fibrosis, and the failure of regeneration that results in a progressively worsening clinical status. The literature is rich in evidence supporting oxidative radical damage to myofibers,35–38 inflammation,39–45 abnormal calcium homeostasis,36,46–50 myonuclear apoptosis,51–57 abnormal fibrosis, and failure of regeneration.58–66 The following is a brief summary of the current understanding of how these processes occur. Mechanical Membrane Fragility Dystrophin is a link between the intracellular cytoskeleton and the extracellular matrix. The carboxy-terminal of dystrophin is attached to the sarcolemma, the surface membrane of striated muscle cells,67–70 binding to b-dystroglycan71 and through this to other dystrophin-associated glycoproteins, and to a-dystroglycan, which links the sarcolemma to the extracellular matrix.72 When dystrophin is not present, the disconnection of contractile proteins from b-dystroglycan results in loss of b- and a-dystroglycan and the DGC from the sarcolemma. This disruption results in membrane fragility and abnormal permeability, particularly to calcium ions. Abnormal Permeability to Calcium and Chronic Increase in Intracellular Calcium In addition to the membrane disruption theory, there is accumulating evidence that abnormal Ca2þ handling may be related to direct dystrophin regulation of mechanosensitive transient receptor potential (TRP) channels47,73 as well as abnormal intracellular Ca2þ cycling.74–76 The deregulation of Ca2þ channels is seen in abnormal function of voltage-insensitive or “stretch-activated” Ca2þ channels, a subfamily of the TRP channels.77 These stretch-activated channels are abnormally active under mechanical stimulation in myotubes of mdx mice (murine model of DMD), resulting in an increase in intracellular calcium.73,78,79 The L-type, voltage-gated Ca2þ channels also appear to be abnormal in the absence of dystrophin; it has been shown that the Ca2þ currents in response to an action potential are much smaller in mdx mice than in normal controls. A disrupted direct or indirect linkage of dystrophin with these channels may be crucial for proper excitation-contraction coupling, initiating Ca2þ release from the sarcoplasmic reticulum. The abnormal intracellular Ca2þ levels result in abnormal activation of Ca2þ-activated proteases (i.e., calpain) with subsequent abnormal degradation of intracellular proteins, which probably contributes to the abnormal functioning of the calcium leak channels.80 Recent evidence shows that exercise worsens the abnormalities in calcium homeostasis in mdx mice.81 This finding supports the clinical observation that eccentric exercises in DMD are deleterious and exacerbate muscle weakness.82,83 Calcium also accumulates in mitochondria, contributing to cell dysfunction by affecting energy production.46 Abnormal Immunologic Response A persistent inflammatory response is observed in dystrophic skeletal muscle. Mechanical stretch can abnormally activate nuclear factor kappa-beta (NF-kB), resulting in increased expression of the inflammatory cytokines interleukin-1b and tumor necrosis factor-alpha (TNF-a).84 The extracellular environment is marked by an increased presence of inflammatory cells (i.e., macrophages) and elevated levels of various inflammatory cytokines (i.e., TNF-a, transforming growth factor-beta [TGF-b]). The presence of these substances, which lead to successful muscle repair in healthy muscle, may promote muscle wasting and fibrosis in dystrophic muscle.

347

Many of these immune response pathways are known to be blocked by prednisone, which is known to slow progression of the disease. These include induction of the transcription of NF-kB inhibitor, which keeps NF-kB in the inactive state; and decreased production of pro-inflammatory cytokines and induction of genes that inhibit cyclo-oxygenase-2, adhesion molecules, and other inflammatory mediators. Abnormal Signaling Functions Mounting evidence shows that the dystroglycan complex has important muscle cell signaling functions, and its integrity is essential for muscle cell viability.85 These functions include transmembrane signaling (through b-dystroglycan), docking of signal transduction molecules (i.e., caveolin-3), and interaction with or regulation of other transmembrane complexes (i.e., integrins). When the dystroglycan complex is disassociated from the sarcolemma, there is a disruption of the cell signaling involved in regulating apoptosis85 and in the metabolism of reactive oxygen species.36,37,84,86–88 Another abnormality of cell signaling is likely the underlying explanation for the “vascular” theory of DMD pathogenesis, supported in the past by morphologic evidence of muscle fiber group necrosis occurring very early in the disease, presumably secondary to ischemia. Recent findings show that the mislocalization and reduction of neuronal nitric oxide synthase (nNOS) in dystrophic muscle affects smooth vessel vasodilation in response to alpha-adrenergic stimuli in exercise,89 resulting in muscle ischemia.90 Dystrophin-associated a-syntrophin appears to be essential for the membrane localization of nNOS.89 Abnormal Fibrosis and Muscle Regeneration Fibrosis (excessive deposition of endomysial and perimysial extracellular matrix) is a known secondary phenomenon to chronic muscle inflammation and fiber degeneration in DMD.44 However, the amount of fibrosis in DMD seems disproportionate to the clinical severity in the earlier stages of the disease. Observation of this fact spurred the idea that fibrosis may also occur independent from muscle necrosis and degeneration. Evidence suggests that both enhanced fibrinogenesis and decreased fibrinolysis91 are implicated in the development of muscle fibrosis in DMD. It has been established that expression of the fibrogenic cytokine TGF-b1 is increased in the muscle of DMD patients59 and in serum samples of individuals with DMD.92 Diagnosis and Evaluation Clinical Characteristics Duchenne Muscular Dystrophy

Neuromuscular Involvement Muscle fiber necrosis with elevated muscle calcium levels and a high serum creatine kinase (CK) enzyme level can be found in infancy in patients with DMD,93 but the clinical manifestations are typically not recognized until at least age 3 years. This discrepancy represents a potential therapeutic window in which early interventions could theoretically prevent or delay the onset of symptoms. Walking often begins later than in normal children, and affected boys experience more falling than expected. Gait abnormality often becomes apparent by age 3 to 4 years, leading to clinical evaluation. Muscle weakness presents initially in neck flexor muscles, with power being less than antigravity. As a result, the child turns on his side when getting up from a supine position on the floor, which is the initial sign of the Gowers maneuver. Hypertrophy of calf muscles becomes prominent by age 3 or 4 years (Fig. 19-3). Hypertrophy of other muscles, including the vastus lateralis, infraspinatus, deltoid, and less frequently the gluteus maximus, triceps, and masseter muscles, may also

348 Treatment and Management of Specific Neuromuscular Disorders

mildly symptomatic. Respiratory complications and their treatment are discussed in greater detail in Chapter 2. Cardiac Involvement Boys with DMD are at risk for cardiomyopathy, especially if they have deletion of exons 48 to 53.95 Mild degrees of cardiac compromise in DMD may occur in up to 95% of boys.96 Chronic heart failure may affect up to 50%.96,97 Sudden cardiac failure can occur, especially during adolescence. In one series of 19 patients, autopsies revealed that 84% had demonstrable cardiac involvement.98 Cardiac complications and their management are discussed further in Chapter 3. Neuropsychological Involvement Overall, the IQ curve in boys with DMD is shifted to the left.99 The mean IQ score in one study was 83 (range, 46 to 134). Other studies have not been able to prove a difference in overall IQ.100–103 Recently, it has become evident that certain cognitive areas (i.e., verbal memory) are more affected than others in DMD.102 Other Organ Involvement Rarely, gastrointestinal tract involvement associated with smooth muscle dysfunction causes megacolon, volvulus, abdominal cramping, and malabsorption.104

A

B Clinical Characteristics of Becker Muscular Dystrophy

Figure 19-3 A child with Duchenne muscular dystrophy. Notice winging of the scapulae (A), hypertrophy of the calf muscles, and prominent lordosis (B).

develop. Muscle mass is usually decreased in later stages in the pectoral, peroneal, and anterior tibial muscles. Because of hip girdle weakness, untreated patients exhibit the Gowers sign by age 5 or 6 years. The patient assumes a lockedleg, buttocks-first position followed by pushing off the floor with the hands, literally pushing the trunk erect by bracing the arms against the anterior thighs. Patients also tend to rock from side to side when walking, producing the waddling gait that is typical in older boys with the disease. Climbing stairs also becomes difficult with disease progression, and eventually distal muscles of the arms and legs become weak. Accelerated deterioration in strength and balance often results from intercurrent disease or surgically induced immobilization. A wheelchair is required when ambulation is no longer possible, typically near the end of the first decade in untreated DMD and about 3 to 10 years later in steroid-treated DMD. After loss of ambulation, contractures become more pronounced in the lower extremities; they also soon involve the shoulders, and kyphoscoliosis may develop. Cardiac and respiratory involvement often occurs in this later disease stage as well. Adolescent patients manifest increasing weakness and are unable to perform routine daily tasks with their arms, hands, and fingers. The head may progressively flex forward as extensor neck muscles lose strength. Lower facial muscles may be involved in the advanced phase. Respiratory Involvement Pulmonary function becomes compromised because of weakness of intercostal and diaphragmatic muscles and severe scoliosis. It occurs later in the disease in nonambulatory boys and is the primary cause of mortality in DMD. Muscle weakness affects all aspects of lung function, including mucociliary clearance, gas exchange at rest and during exercise, and respiratory control during wakefulness and sleep.94 It is important to recognize that DMD is often associated with sleep disordered breathing, which could be asymptomatic or only

Becker muscular dystrophy is present in 3 to 6 per 100,000 male births.105 The onset of weakness is later than in the Duchenne type, usually seen after age 7 years and often in the second decade; the disease is also marked by lordosis, calf hypertrophy, and other features of DMD of a milder phenotype (Fig. 19-4). The course is prolonged into adulthood, often with a normal life span. Ambulation is typically maintained beyond age 30 years. CK level is usually between 2000 and 20,000 U/L but may be in the normal range for mildly affected males. Because these patients can be asymptomatic for decades, they commonly are misdiagnosed as having liver disorder

A

B

Figure 19-4 An adult patient with Becker muscular dystrophy. A, Patient’s front; B, patient’s back. Notice the prominent calf muscles.

Treatment and Management of Muscular Dystrophies

349

when routine laboratory values show elevated transaminases (AST and ALT), which are elevated in parallel with serum CK levels. At times, the BMD diagnosis is made after many years of gastrointestinal follow-up for elevated transaminases, until someone thinks of measuring the CK, which comes back extremely elevated. The patient may have undergone liver biopsies to no avail. Pseudohypertrophy, proximal hip weakness resulting in the Gowers sign, and electrocardiogram (ECG) abnormalities associated with DMD are also common to BMD.

effective for the molecular diagnosis of common deletions (60% of patients); however, it cannot be used to identify duplications, other point mutations, intronic mutations, or to genotype female carriers. Other diagnostic approaches, such as quantitative PCR113,114 or multiplex amplifiable probe hybridization,115 might be used for accurate diagnosis and for carrier testing. With more recent technology, it is now possible to screen the entire DMD gene to search for the specific molecular defects responsible for the other 40% of DMD and BMD.

Chromosome Xp21 Microdeletion Syndromes

Muscle Biopsy Histology of DMD muscle demonstrates fiber size variation, degenerating and regenerating fibers, clusters of smaller fibers, endomysial fibrosis, and a few scattered lymphocytes. Large, opaque fibers are prominent on modified Gomori-Wheatley trichrome staining (Fig. 19-5). As the disease progresses, muscle fibers are lost and replaced with fat and connective tissue. Fiber typing with adenosine triphosphatase histochemistry is less distinct than expected. Oxidative histochemistry is maintained. Absence of immunoreactivity for dystrophin with monoclonal antibodies against the C-terminal, rod domain, and N-terminal are necessary for accurate diagnosis of DMD (Fig. 19-6). Quantitative dystrophin analysis by immunoblot

The Xp21 microdeletion syndromes are a series of syndromes that include DMD, Aland Island eye disease, adrenal hypoplasia, glycerol kinase deficiency, retinitis pigmentosa (RP3), mental retardation (MRX1), and ornithine transcarbamylase deficiency. The combination of these conditions led to the discovery of the DMD gene on Xp21.106 Female DMD Carriers and Manifesting Carriers

Carrier females are heterozygous with a normal DMD gene on one X chromosome and a mutant gene on the other. More than 90% of female carriers are asymptomatic. However, variable degrees of muscle weakness may be seen with skewed X-inactivation, in which more than half of the mutant X chromosomes are operant in muscle cells. Such cells are prone to degeneration. If a large number of abnormal muscle fibers are present in a given muscle, that muscle may display weakness. The degree of strength from one muscle to another may vary from normal strength to significant weakness. Signs and symptoms of female dystrophinopathy include muscle weakness, myopathic findings on muscle biopsies, elevated CK levels, and partial absence of dystrophin in muscle.107 Symptoms manifest in about one fifth of DMD carriers.108 The diagnosis should be considered in women with elevated CK levels and muscle weakness, even in the absence of a positive family history for DMD.109 Duchenne muscular dystrophy carriers appear to have an increased incidence of cardiomyopathy. Studies have shown an incidence of asymptomatic cardiomyopathy ranging from 8% to 48% in adult DMD carriers108,110,111 and from 0% to 15% in DMD carrier girls under age 16 years.112

A

Clinical Laboratory Tests In DMD, serum CK is greatly elevated, typically from 10,000 to 30,000 U/L, early in the course of the disease. Gaps in the sarcolemma allow efflux of the enzyme into the circulation. Serum CK levels can vary greatly with activity and decrease as muscle mass is lost with disease progression. There is no correlation between the serum CK level and clinical severity in DMD, and use of CK levels as a surrogate marker of treatment response is not well supported. Because of the leakage of intracellular muscle proteins, other muscle isoenzymes also increase in the circulation. These include aldolase, lactate dehydrogenase, ALT, and, to a lesser degree, AST. Genetic Testing Genetic testing for DMD and BMD is widely available, especially for the deletions in the two “hot spots” of the gene. The screening of only 19 exons by multiplex polymerase chain reaction (PCR) identifies approximately 98% of all deletions.19 Southern Blot analysis is utilized to predict if the deletion, when in the rod domain, will shift the reading frame, and thus is conclusive for DMD or BMD. However, when the deletions are in the first 25 exons, there are enough exemptions to the “reading frame” rule112a that muscle biopsy is necessary to determine with accuracy whether the patient has Duchenne or Becker muscular dystrophy. This technique is very

B Figure 19-5 A, A trichrome-stained section of a muscle biopsy from a patient with Duchenne muscular dystrophy showing necrosis, opaque fibers, mildly increased endomysial connective tissue, and variation in muscle fiber size (200). B, Higher magnification (400) showing fiber atrophy, hypertrophy and necrosis, and interstitial infiltrates of mononuclear cells. (Reproduced with permission from Bertorini T: “Muscular Dystrophies” in Pourmond’s Neuromuscular Diseases, Expert Clinicians’ Views, Boston, 2001, ButterworthHeinemann.)

350 Treatment and Management of Specific Neuromuscular Disorders

A

B

C

Figure 19-6 Muscle biopsy of Duchenne muscular dystrophy showing staining for dystrophin with absence of the protein (A) compared with control muscle (B) showing normal staining for dystrophin and muscle atrophy. (C) An area of the muscle biopsy showing scattered revertant fibers that stain positive for dystrophin (200).

Figure 19-7 Electromicrograph of a specimen from a 6-year-old child with Duchenne muscular dystrophy revealing sarcolemma (cell wall) disruption (arrows) with redundant membranes (10,800). (Reprinted with permission from Escolar D: “Muscular Dystrophies” in Pediatric Neurology Principles & Practice, Philadelphia, 2006, Mosby.)

is more accurate for diagnosis than immunostaining, with dystrophin value being less than 5% in DMD patients. On electron microscopy, gaps in the sarcolemma with preservation of the basement lamina are seen in nonnecrotic fibers (Fig. 19-7). Histologic findings in BMD are similar to but less pronounced than those in DMD. The sarcolemmal gaps are not as readily seen. Using monoclonal antibodies directed to separate regions of dystrophin, immunoreactivity over the sarcolemma shows a variety of staining patterns, ranging from intact to absent, with one or more antibodies.116 Treatment and Management In DMD and BMD, multidisciplinary care involving physicians (neurologists, physiatrists, orthopedic surgeons, cardiologists, and pulmonary medicine specialists), physical and occupational therapists, nutritionists, exercise physiologists, and social workers is important for the overall well-being of the child and the family. Pharmacologic Treatment Daily prednisone stabilizes or improves the strength of boys with DMD and is the only proven treatment for this disease. The benefits of this drug were first reported in an open trial of 2 mg/kg/day,117 later reinforced by other open design trials118,119 and subsequent double-blinded, placebo-controlled trials.120–122 The most effective dose is 0.75 mg/kg/day. There is a dose-response effect, with the lowest effective dose being 0.3 mg/kg/day.120 Effects on strength can be observed as soon as 10 days after treatment starts, with a peak at 3 months and then a stabilization period.123 In a 3-year follow-up

study, improvement was maintained in those children who were kept on doses of at least 0.5 or 0.6 mg/kg/day.121 DMD boys treated with prednisone from an earlier age usually remain ambulatory into their teens, have less incidence of scoliosis124,125 and contractures,126 and maintain normal or near-normal respiratory function.125,127–129 Despite the evidence in favor of daily prednisone, a source of major concern for patients and physicians are the numerous potential side effects caused by this treatment. Most commonly seen are increased appetite and weight gain, irritability, hirsutism, cushingoid features, and decreased linear growth.130 In this young population, diabetes, hypertension, ulcers, and infections are rare. Steroidinduced osteoporosis is difficult to assess in DMD, because baseline osteoporosis might be present secondary to decreased activity.131–133 Deflazacort, a corticosteroid not available in the United States, has similar benefits to prednisone but causes less weight gain and cushingoid features, though it appears to have an increased predisposition to asymptomatic cataract formation.127,128,130,134–136 Suggested dosage is 0.9 to 1.2 mg/kg/day. Because of its unavailability, some patients import the drug from other countries. This should only be recommended for those DMD patients who are already overweight before treatment and in a more advanced stage of the disease. Lower dose regimens, including alternate-day corticosteroids and treatment for the first 10 days of the month, have not demonstrated sustained efficacy.121,137 Accumulating evidence suggests that treatment of DMD should start as soon as the diagnosis is made,129,138,139 but early corticosteroids are associated with significant decrease in linear growth. However, this might be a mechanical advantage for DMD boys. A pilot study of 10 mg/kg given over 2 consecutive days of the week (Friday and Saturday) showed that DMD boys improved muscle strength and function while maintaining linear growth, and they did not have increased body mass index compared with untreated DMD boys.140 A larger study comparing both dosing regimens was completed by the Cooperative International Neuromuscular Research Group (CINRG) at the end of 2007. Preliminary results were presented at scientific meetings, but the results of this trial have not yet been published. This study will clarify many questions associated with both regimens concerning appropriate onset of treatment at different stages of the disease and the side effects of steroids in this specific population. Obesity is often a major problem in DMD, even if no steroids are used. For uncertain reasons, patients gain excessive weight, which often becomes apparent before ambulation is lost. The obesity becomes more prominent after confinement to a wheelchair. Boredom, diminished physical activity, and depression may lead to inappropriate food intake,141 and rigorous measures are required to forestall weight gain. Obesity reduces the period of walking capability, hastens scoliosis, and fosters respiratory and cardiac insufficiency. Therefore, if steroid treatment is offered, these patients need to follow

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a restricted caloric intake diet to prevent excessive weight gain. A diet high in proteins, fresh fruits, and vegetables and low in fat and carbohydrates is ideal. A nutritionist should be part of the medical team of a DMD boy receiving long-term steroid treatment. Other immunosuppressive medications have mixed results in DMD. Azathioprine demonstrated no benefit,122 but cyclosporin A showed evidence of efficacy in DMD in an uncontrolled trial.142,143 At 5 mg/kg/day, it showed improvement in strength in a test on an isolated muscle. A randomized, controlled, blinded trial of creatine monohydrate and glutamine supplementation in ambulatory DMD patients (ages 5 to 11 years) was also negative based on manual muscle testing (primary outcome). However, there were consistent and clear trends toward improvement in isometric muscle strength in older patients with creatine, and increased function in younger children with creatine and glutamine.144 Other studies have shown increase in muscle strength and body mass index with creatine in DMD.145,146 No significant side effects were seen with doses of 5 g/day for at least 6 months.144 Another open label pilot study conducted by CINRG demonstrated a possible beneficial effect of coenzyme Q10 as an add-on to traditional corticosteroid therapy. These results have not yet been published. A regimen of prednisone 0.75 mg/kg/day for 10 days alternating with 10-day steroid-free periods is currently being utilized by some physicians in Europe. One retrospective study of this regimen was perfomed147; the benefit over daily or high-dose weekend schedules is unclear. A direct prospective comparison of all three regimens would be useful. Current Research in Pharmacologic Approaches Better understanding of the pathophysiology of dystrophinopathies has provided three main areas of interest for researchers: (1) manipulation of the DMD gene with either repair or replacement; (2) upregulation of proteins that may compensate for a lack of dystrophin; and (3) pharmacologic manipulation of the downstream events that occur when dystrophin is absent or reduced (Fig. 19-8). Several approaches at these different levels have been investigated, and more are currently being evaluated. Most of the preclinical experiments have been performed in the mouse model of muscular dystrophy (mdx), but overall there have been mixed results in the transfer of results from mouse to human.

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Gene Repair or Replacement A small percentage of patients with DMD have nonsense mutations that promote premature translational termination of the dystrophin protein. The result is a small unstable protein that gets rapidly degraded. A new pharmacologic approach to treat DMD aims to “skip” these premature stop codons. Gentamicin, an aminoglycoside antibiotic, has been investigated based on its binding of the ribosome causing “read-through” of premature stop codon (nonsense) mutations. It was tried first in the mdx model of DMD148 and then in a clinical trial on four DMD/ BMD patients.149 Although the mdx experiments showed positive dystrophin in approximately 15% of previously negative muscle fibers,148 the human trial was unable to duplicate this finding. An unrelated drug with a similar mechanism of action (forced read-through of premature stop codon mutations), PTC124 (Ataluren) is currently under investigation in DMD boys. This oral medication can cause suppression of premature stop codons at much lower doses (from 10-fold to 100-fold lower) than gentamicin.150 A randomized, placebo-controlled, dose-finding phase II study was recently stopped because the study failed to show statistically significant improvement in its primary outcome, the 6-minute walk test (6 MWT). Results of the study have not yet been published. Another approach to gene repair includes the delivery to dystrophin-deficient cells of RNA-DNA oligonucleotides that target the specific mutation and revert it to the normal sequence (chimeroplasts),151 or the delivery of antisense RNA molecules to dystrophin-deficient cells so that semi-functional dystrophin can be produced.152–156 This method forces the splicing machinery of the cell to skip the DMD gene exon that contains the gene mutation, which results in the full translation of dystrophin mRNA (minus the mutant exon) into an “in-frame” semi-functional dystrophin protein. A recent trial of an antisense oligonucleotide (PRO051) injected into the tibialis anterior muscles of four DMD patients demonstrated evidence of some sarcolemmal dystrophin in 64% to 97% of muscle fibers. The quantitative ratio of dystrophin to laminin-a2 was 17% to 35% of that seen in controls.157 A phase II/III systemic delivery of PRO051 by subcutaneous infection in DMD is ongoing. A recent study showed that long-term administration of antisense oligonucleotides into the paraspinal muscles of mdx mice reduced dystrophy-related kyphosis. Systemic delivery of another type of AON with a different chemistry

DNA (gene editing ex vivo with AON, then autologous cell transplantation) Gene repair or replacement

Gene replacement (AAV, myoblast transfer) RNA splicing (exon skipping with AON) Translation: stop codon read through (AON,AG, other antibiotics, PTC124 [Ataluren])

Upregulation of compensatory proteins

Blocking downstream effects

Utrophin, -dystrobrevin, -7 integrin, GALNAc, NOS, etc.

Block abnormal Ca influx: stretch channel blockers Fibrosis: antifibrotics Immune: steroids, TNF- antagonists, TGF- antagonists, NFkB pathway modulators Increase NO: arginine-like drugs Increase muscle energy: creatine/CoQ10 Increase muscle regeneration: MYO-029, IGF, glutamine, ACE-031 Antioxidants Others

Figure 19-8 Different treatment approaches in Duchenne muscular dystrophy, including gene repair, replacement, and upregulation of compensatory proteins and modification of downstream effects. AAV, adeno-associated virus; AG, aminoglycosides; AON, antisense oligonucleotides; PTC124, (Ataluren); ATb, antibiotic; CoQ10, coenzyme Q10; DNA, deoxyribonucleic acid; GALNAc, N-acetylgalactosamine; IGF, insulin-like growth factor; MYO-029, NFkB, nuclear factor kB; NO, nitric oxide; NOS, nitric oxide synthase; RNA, ribonucleic acid; TGF, transforming growth factor; TNF, tumor necrosis factor.

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backbone (morpholino) in dystrophic dogs restored dystrophin and produced clinical improvement, opening the doors for trials in humans.158,159 The first morpholino AON proof of concept trial, also targeting exon 51, has been completed in DMD boys. The local intramuscular injection of this AON showed significant increased dystrophin in muscle biopsies.159a A systemic intravenous administration phase II trial is ongoing. Another area of interest is the delivery of functional mini-DMD genes to replace the missing dystrophin, using adeno-associated viral (AAV) vectors. Dystrophin can be produced, the immune response can be prevented, and improved function and pathology in young and older animals has been achieved.160–163 An important hurdle was crossed when systemic delivery of an AAV6 vector with a mini-DMD gene was achieved in the older mdx mouse.164 Recent attempts at vector-mediated mini-DMD gene expression in GRMD (Golden Retriever muscular dystrophy) dogs have caused a significant immune response; therefore, a canine mini-dystrophin gene was developed and was investigated in mdx mice before transfer into GRMD dogs was attempted. The canine mini-dystrophin gene caused expression of dystrophin, improved both fibrosis and central nucleation, and improved the plasma membrane integrity of myofibers in mdx mice.165 The first U.S. clinical trial of mini-DMD gene transfer into humans began in 2006 and is currently underway. Finally, the transfer of myoblasts and other stem cells have been studied as an attempt to introduce the normal DMD gene, but these approaches have not yet been very encouraging.165 Myoblast transplants were tried in DMD boys with no success,166–169 although they were effective in mdx mice.170 New muscle cell precursor populations have since been identified, including the recently described “satellite side population (SP) cells,”171 which may be the precursors of the muscle-repair “satellite cells.” In mdx mice, these SP cells have been more efficient in engrafting into muscle fibers than the more mature cells used in previous trials, and the mice demonstrated extensive muscle regeneration and dystrophin production. Up-regulation of Compensatory Proteins Although the ultimate target for a cure in DMD is normalized expression of dystrophin, several other structural proteins have been proven to have at least a modifying effect on the disease. Utrophin is a sarcolemmal protein with a structure very similar to that of dystrophin. Transgenic overexpression of both truncated and full-length utrophin protein in mdx mice has demonstrated a significant improvement in phenotype.172–174 Up-regulation of utrophin by pharmacologic means has been investigated. Prednisone is known to up-regulate utrophin; arginine also has been shown to do the same.175 At least one drug is in development for future studies. The a7b1-integrin protein is an alternative to the DAG, attaching the muscle fiber to laminin in the basal lamina. Transgenic expression of this protein in dystrophin- and utrophin-deficient mice has shown improvements in life expectancy and a reduction of muscle pathology.176 Poloxamer 188 (P188) is an amphiphilic polymer that acts as a synthetic sealant by localizing into damaged portions of membranes.177 A recent study in mdx mice showed strong evidence of improvement in cardiomyopathy when P188 was administered.178 However, similar results have not been reliably achieved in skeletal muscle.179 Several other types of proteins have shown the ability to compensate for the loss of dystrophin outside the arena of structural integrity. For instance, myostatin, the protein that negatively regulates muscle growth, has been targeted as a potential modulator of dystrophinopathies. Early studies on myostatin inhibition in mice were encouraging,180 but an initial human trial using anti-myostatin antibodies did not demonstrate clinical effectiveness.181 Efforts have

also been focused on a related protein, follistatin, which is an endogenous inhibitor of myostatin. The transgenic expression of follistatin has demonstrated increased muscle mass and a decrease in signs of disease on histology in mdx mice.182 A correlation has been observed between calcium-dependent protease (calpain) activity in dystrophic muscle and muscle necrosis.183 Calpastatin is a specific endogenous inhibitor of two types of calpain, and transgenic overexpression of calpastatin has demonstrated a reduction in muscle necrosis.184 As indicated above, the absence of dystrophin results in mislocalization of the nNOS protein and its absence from the membrane. Transgenic expression of nNOS in mdx mice has demonstrated reduced inflammation and necrosis in both skeletal and cardiac muscle.185 Modification of Downstream Events After an almost 15-year gap in which all efforts were focused on a definite cure with gene therapy, there has been an explosion of clinical studies to evaluate new pharmacologic approaches to treat DMD. The CINRG has completed several clinical trials for DMD over the past 2 years, besides the creatine study mentioned above. A study comparing daily prednisone (0.75mg/kg/day) against a weekly pulse of 10 mg/kg divided over 2 days had the objective of determining if a different dose schedule could be as effective as daily prednisone but with lesser side effects. This study was also designed to evaluate the effect of steroids on bone density and behavior after 1 year of treatment. There was equal randomization to younger and older patient groups, so that the study could suggest if efficacy and side effect profile differs by age or stage of disease. The results of this study have not yet been published. Novel pharmacologic approaches at modifying downstream events associated with dystrophinopathies are also under investigation and development. Intracellular Calcium L-type voltage-dependent calcium channel blockers such as diltiazem and verapamil have shown some benefit in mdx mice, including decreased CK levels and decreased permeability of the sarcolemma in the diaphragm.186 However, to date no human trials have demonstrated significant benefit of this drug class in DMD.187 Blockage of stretch-activated channels has been achieved by the nonselective TRP blockers gadolinium and streptomycin, as well as by the selective cationic TRP blocker GsMTx4 (spider venom toxin), and has resulted in normalization of intracellular calcium and muscle force generation ex vivo in mdx mouse muscle.188,189 Furthermore, treatment of mdx mice with oral streptomycin resulted in decreased muscle necrosis, which opens the door for clinical translation.188 Pentoxifylline, a phosphodiesterase inhibitor, has recently been demonstrated to counteract the voltage-independent calcium channel overactivity in mdx mice190 and has shown increased resistance to exercise in mdx mice and increased tetanic tension of strips of diaphragm muscle taken from treated mice. Pentoxifylline also has antifibrotic, anti-inflammatory, and antioxidant actions. A pilot study looked at the effect of pentoxyfilline in young (ages 4 to 7 years), steroid-naive DMD boys. A liquid, immediate-release formulation was used, with a dose of 20 mg/kg. The main purpose of the study was to evaluate safety of the drug in this young child population and to determine any effect on overall muscle strength. A larger, controlled study evaluated the effect of adding pentoxifylline (long-release, FDA-approved form) to steroid-treated DMD boys age 7 and older. Both studies have been presented in scientific meetings, but have not yet been published.

Treatment and Management of Muscular Dystrophies

Dantrolene, which inhibits calcium release from the sarcoplasmic reticulum, has been shown to improve function in mdx mice and in a small clinical trial decreased muscle spasms and CK in patients with DMD.191 Abnormal Immune Response The inflammation activated NF-kB pathway is a potentially favorable target for treatment. Genetic alteration of various members of this pathway in mdx mice have shown favorable results, as has the administration of a soluble inhibitor of the pathway.192 Blockade of the related TNF-a pathways has also produced favorable results in mice.193 The beneficial effects of prednisone in DMD are thought to be partly related to inhibition of this pathway. Abnormal Signaling Functions Efforts to ameliorate the effects of reactive oxygen species are currently under investigation. One promising compound along these lines is idebenone (SNT-MC17), which incorporates into the mitochondrial membrane, improving respiratory chain function and inhibiting lipid peroxidation and thus decreasing oxidative stress. When given presymptomatically and long term to mdx mice, it prevented cardiac diastolic dysfunction and the development of lethal acute heart failure.194 Another approach being studied is the activation of the nitric oxide (NO) pathway, which is impaired in DMD. A compound named HCT 1026 combines NO activation with nonsteroidal anti-inflammatory activity. The administration of this drug improved morphologic and functional features of mdx mice.195 Similar NO donor compounds have been shown to cause a down-regulation of the histone deacetylase HDAC2 in dystrophic muscle.196 This finding may represent a role for such proteins in the pathogenesis of Duchenne muscular dystrophy. Abnormal Fibrosis and Muscle Regeneration The abnormal fibrosis seen in DMD muscle is targeted by a novel drug called halofuginone. This compound inhibits TGF-b mediated collagen production. The mdx mice given halofuginone showed increased muscle cell proliferation; improved limb, cardiac, and respiratory function; and better recovery from exercise.197 A class of drugs called deacetylase inhibitors has demonstrated possible utility in DMD; in mdx mice, trichostatin A showed increased myofiber size and improved resistance to exercise-induced degeneration as well as decreased fibrosis and normalized muscle architecture.198 The presumed mechanism of action is an up-regulation of the myostatin inhibitor, follistatin. This group of drugs is readily available in clinical practice and includes valproic acid and phenylbutyrate. Another approach to increase muscle size and decrease fibrosis has now reached the clinical arena. A soluble activin type II receptor attached to the Fc portion of the human gammaglobulin (ACE031) effectively binds circulating myostatin and other negative regulators of muscle growth and fibroblast growth and results in increased lean muscle mass, decreased fibrosis, and increased strength and function in the mdx mouse (Acceleron Pharma, unpublished data). A Phase II clinical trial in DMD boys has been initiated. The angiotensin II type 1 receptor blocker, losartan, has also recently been shown to improve muscle regeneration and function in mdx mice via antagonism of TGF-b activity.199 Respiratory Care Patients with DMD or BMD eventually progress to have ineffective cough and decreased ventilation, leading to pneumonia, atelectasis, and respiratory insufficiency in sleep and while awake.94 These complications are generally preventable with careful follow-up and

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assessments of respiratory function. Patients with DMD should have routine immunizations by a primary care physician as recommended for well children by the American Academy of Pediatrics. In addition, these patients should receive the pneumococcal vaccine and annual influenza vaccine. A polysomnographic study with continuous CO2 monitoring is the best way to assess the need for ventilatory support. Pulse oximetry, especially during the awake state, is suboptimal. The decisions regarding long-term ventilation, be it invasive or noninvasive, should involve the patient, caregivers, and medical teams. Physicians have a legal and ethical responsibility to disclose treatment options and must avoid using their own perceptions of quality of life as the main factor in deciding whether to offer this type of information.200 End of life decision-making should be discussed earlier based on all possible information available to the patient. Further details of respiratory management are provided in Chapter 2. Cardiac Management Although ECG abnormalities are common in DMD, the best correlation of cardiac involvement with prognosis is by measuring left ventricular dysfunction by echocardiography.202 Recent guidelines for the study of cardiac involvement in DMD have been published.203,204 These recommend that DMD patients have an ECG and echocardiography at the time of diagnosis, at every 2 years up to age 10 years, and subsequently every year. The early, preventive use of ACE inhibitors and later b-blockers is recommended.203,204 Cardiac management is discussed in more detail in Chapter 3. Drug Precautions Use of anticholinergic drugs and ganglionic blocking agents should be avoided because of their tendency to decrease muscle tone. Patients with DMD may be susceptible to malignant hyperthermia, and proper evaluation and preparation before administration of general anesthesia are recommended.213 Cardiotoxic drugs, such as halothane, should not be used, and caution is advised in undertaking general anesthesia.214 Details are further discussed in Chapter 10. Rehabilitation No large prospective studies have been performed to evaluate the role of physical therapy, stretching exercises, use of braces, or type of physical activity in DMD. Thus, the evidence is lacking for solid recommendations. These approaches are described further in Chapter 8. Contractures Active range-of-motion exercises supplemented by passive stretching are important to prevent contractures. Nighttime stretching orthoses (similar to the static ankle-foot orthosis, but with a hinge at the ankle and adjustable straps) are useful and should be recommended at age 5 to 6 years. A standing board tilted up 20 degrees may be used for 20 minutes twice a day to provide constant stretching of the Achilles tendons. Keeping the heel cords stretched through vigorous passive stretching by parents and physical therapists helps maintain better gait mechanics. This program requires stretching of the tensor fascia lata, hamstrings, knee flexors, and ankle plantar flexors. If strenuous stretching is not effective, surgical release of tight heel cords may be beneficial,201 even if the quadriceps and gastrocnemius muscle groups are both less than antigravity in strength. In the latter case, long leg bracing can be offered to keep some ambulation after contractures are corrected. Mobilization in a walking cast immediately after surgery is essential to prevent loss of strength. Temporary bracing after surgery is necessary for optimal results after tenotomy procedures. Hip flexion contractures may

354 Treatment and Management of Specific Neuromuscular Disorders

benefit from surgical release followed by application of long leg braces. Resection of the fascia lata (Rideau procedure) may be beneficial for some patients.201 Scoliosis Nearly all patients with DMD develop scoliosis after losing independent ambulation. The use of solid seat and back inserts in properly fitted wheelchairs is helpful in preventing scoliosis by keeping truncal posture erect. For some boys, long leg braces can be fitted to allow braced upright daily standing to prevent curvature. Baseline back x-ray films to document the degree of curvature if scoliosis begins to develop should be obtained for comparison with future films. The use of steroids, perhaps because it prolongs ambulation beyond the growth spurt of the early teen years, delays or prevents scoliosis, even if the child is eventually wheelchair bound.124,126 Surgical management of scoliosis and other orthopedic complications is discussed in Chapter 9. Genetic Counseling Duchenne and Becker muscular dystrophies are inherited in an X-linked recessive manner; the risk to the siblings of a proband depends on the carrier status of the mother. Carrier females have a 50% chance of transmitting the DMD mutation in each pregnancy. Sons who inherit the abnormal gene will be affected, whereas daughters will be carriers. Males with DMD do not reproduce. However, males with BMD and X-linked dilated cardiomyopathy may reproduce. All of their daughters will be carriers but none of the sons will inherit their father's DMD mutation. Prenatal testing for pregnancies at risk is possible. Until the molecular genetics of DMD and BMD were understood, the diagnosis of maternal and female sibling carriers was based on pedigree analysis and indirect assays. These included serum CK level determinations,205,206 the occasional finding of histologic abnormalities in muscle obtained from carriers,207 and in vitro muscle ribosomal protein synthesis.208–210 Today, the specific molecular characterization of a proband makes genetic counseling much easier. If a specific mutation is found in a boy with DMD or BMD, genetic testing of the mother or sister looking for the exact mutation will determine if she is a carrier, and appropriate counseling can be done for further pregnancies. When DNA analysis in the proband is not informative, muscle biopsy of the fetus can be used to make the diagnosis.211 Study of muscle from male fetuses with DMD show morphologic changes by the second trimester, especially greater muscle nuclear size when compared with fetuses of the same gestational age.212 Immunoreaction for dystrophin is absent. When a deletion or specific mutation in the DMD gene has been demonstrated in another family member, the deletion may be looked for in fetal issue or earlier in chorionic villus. This means that intrauterine diagnosis is possible by 7 weeks' gestation in suspect male embryos. Emotional and Behavioral Management Dysthymic disorder and major depressive disorder can occur in DMD boys, especially in the adolescent.215,216 An affected boy's preoccupation with self and subsequent withdrawal may lead many families to seek counseling. Depression may be seen in a boy who has lost an older brother or close friend to DMD. Depression is often associated with intellectual limitation, which may induce low tolerance for frustration and overstress other manifestations of emotional immaturity. Psychological evaluation and counseling may be necessary. Neuropsychological screening for intellectual deficits and behavioral problems is ideally done as the boy enters school and should be repeated in preadolescence.

Limb-Girdle Muscular Dystrophies The limb-girdle muscular dystrophies (LGMD) are characterized by progressive muscle weakness of the large muscles around the shoulder and pelvic girdles (Fig. 19-9). The recent identification of individual causative mutations has led to a more thorough picture of the phenotype, but a confusing nomenclature has developed. The initial classification of these disorders was based on the mode of inheritance, dividing them into autosomal dominant (type 1: LGMD1), autosomal recessive (type 2: LGMD2), and X-linked forms. With the expanding list of identified genes, we now have a list of eight dominant forms (LGMD1A to LGMD1H), and fourteen recessive forms (LGMD2A to LGMD2N). An integrated classification taking into account the type and localization of the proteins was recently proposed.1 The following is a summary of some of the better understood limb-girdle dystrophies. Limb-Girdle Muscular Dystrophy 1C: Caveolinopathy Caveolins are small transmembrane proteins with intracellular domains that undergo extensive oligomerization to form membrane complexes known as caveolae. Skeletal muscle disorders result from mutations in the gene that encodes caveolin 3 (CAV3), localized to chromosome 3p25. This protein interacts with nNOS and the dystrophin-associated protein complex via the intracellular portion of b-dystroglycan.217,218 The disease can present in childhood with a range of symptoms from simple exertional myalgias to slowly progressive weakness, calf hypertrophy, and CK elevation. CAV3 mutations are also associated with autosomal dominant rippling muscle disease. Limb-Girdle Muscular Dystrophy 2A: Calpainopathy This childhood-onset LGMD has been reported as the most frequent autosomal recessive LGMD in several series.219–222 The abnormal protein, calpain 3, is a nonlysosomal intracellular, muscle-specific, Ca2þ-activated neutral protease.223 LGMD 2A was the first form of limb-girdle dystrophy identified that is caused by deficiency of a nonstructural protein. The calpain 3 gene (CAPN3) is located to chromosome 15q15.1– q21.1 and consists of 24 exons extending over a genomic region of

Figure 19-9 A patient with limb-girdle muscular dystrophy showing wasting of the thigh muscles and winging of the scapulae.

Treatment and Management of Muscular Dystrophies

50 kb.224,225 Homozygous null-null mutations appear to have the most severe phenotype, in terms of earlier wheelchair need, whereas a heterozygous missense mutation has the milder phenotype.226 CAPN3 appears to be a cytoskeleton modulator with an important role in muscle maturation.227 One current hypothesis is that calpain could have a protective effect and be involved in muscle detoxification, preventing a degradation of the muscle fiber.228 It may also play a role in intracellular signaling pathways, and its deficiency might be associated with myonuclear apoptosis by deregulation of the NF-kBa inhibitor/NF-kB pathway.229 Under normal circumstances, CAPN3 undergoes rapid autocatalytic activity after translation.230 During the short minutes (less than 5 minutes in muscle cultures) that the protein is present, it is in a resting state unless it becomes activated by signaling mechanisms.231 The autocatalytic activity resides in a Ca2þ-sensitive region between domains II and III of the protein. LGMD2A has a characteristic phenotype in approximately 64% of genetically confirmed patients. Interfamilial and intrafamilial variability, though, is not uncommon.228 Age of symptom onset is between 2 and 49 years, with a mean age of presentation of about 14 years (8).226 The disease causes symmetric weakness of the pelvic and shoulder girdle muscles. Cardiac muscle is not affected. Scapular winging can be seen early.232 Most patients, regardless the age of onset, become wheelchair bound about 25 years after symptom onset. The CK level is elevated by 5-fold to 20-fold. Cognition is not impaired. The diagnosis of calpainopathy is based on a typical phenotype, a muscle biopsy showing Western blot abnormalities and a genetic test showing two mutations on two alleles. The combination of a typical phenotype with an abnormal Western blot in muscle biopsy (at least 2 abnormal bands) brings the probability of being calpainopathy to 90%.226 However, if one of these tests is missing, the probability of accurate diagnosis is reduced to about 75%.226 A 20% to 40% falsenegative rate on Western blot in these patients indicates that genetic sequencing should be pursued when there is clinical suspicion.226,233 Muscle pathologic findings are positive for necrosis, regeneration, altered myofibrillar architecture, increased centrally placed nuclei, fibrosis, fiber type I predominance, and normal immunoreactivity for dystrophin and a-sarcoglycan. Mild inflammation can also be seen. Limb-Girdle Muscular Dystrophy 2B: Dysferlinopathy Mutations in the dysferlin gene (DYSF) on chromosome 2p13 cause distinct phenotypes of muscular dystrophy: limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), or juvenile-onset distal posterior compartment myopathy, as well as distal anterior compartment myopathy, which are known collectively by the term dysferlinopathy. These conditions represent 1% of recessive LGMD and about 33% of distal LGMD. The DYSF gene encodes a 230-kDa protein with widespread expression in tissues such as skeletal muscle, cardiac muscle, kidney, placenta, lung, and brain. Immunohistochemical studies show that, in skeletal muscle, dysferlin is located at the plasma membrane, as well as in cytoplasmic vesicles.234 This new class of muscular dystrophy is distinct in its pathogenesis in that the defect lies in the maintenance, not the structure, of the plasma membrane. Histopathologic and immunohistochemical studies in these patients show absence of dysferlin.235 In addition, a very active inflammatory and degenerative process is characteristic in this disease and can lead to a misdiagnosis of polymyositis. The features of the immune response are different, though, with macrophages more common than T cells, perivascular and interstitial

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infiltrates consisting of CD8þ and CD4þ cells without B cells, and overexpression of major histocompatibility complex class I on muscle fibers.236 There are two common phenotypes, LGMD2B and the distal posterior compartment myopathy or MM, both presenting in the second decade of life.237 Two other phenotypes, distal anterior compartment and scapuloperoneal types, can also be seen earlier.238 The patients show normal early developmental milestones and no signs in childhood with a slowly progressive muscle weakness and wasting starting in the early to late teens.239 The MM phenotype typically begins in the calves (Fig. 19-10) with later development of proximal weakness. LGMD 2B phenotype shows a predominantly proximal muscular dystrophy. Affected individuals have pelvic girdle muscle weakness, with lower limbs abducted and externally rotated and hyperlordosis as a result of hip muscle weakness. Diagnosis of dysferlinopathy is based on the absence of dysferlin expression on immunoblots or cryostat sections as well as on exclusion of dystrophinopathy, sarcoglycanopathy, calpainopathy, and caveolinopathy. The diagnosis of dysferlinopathy can also be made by measuring dysferlin expression in peripheral blood mononuclear cells by immunoblot analysis, which shows excellent correlation with muscle biopsy findings.240 This test is available commercially. Limb-Girdle Muscular Dystrophies 2C, 2D, 2E, 2F: Sarcoglycanopathies The sarcoglycanopathies are a family of autosomal recessive disorders often presenting with an early and severe phenotype. The four sarcoglycans comprise a tetrameric complex of membrane proteins that contributes to the stability of the plasma membrane cytoskeleton and facilitates the association of dystrophin with the dystroglycans. The four sarcoglycan genes (alpha, beta, gamma, and delta) are related to each other structurally and functionally, but each has a discrete chromosomal location. Mutations in each gene may produce partial or complete loss of the entire complex.241 Patients with sarcoglycanopathies were initially delineated from children with a severe Duchenne-like presentation who proved dystrophin positive and in whom autosomal recessive inheritance was likely.242 The term severe childhood autosomal recessive

A

B

Figure 19-10 A patient with Miyoshi myopathy: front (A); back (B). Notice prominent atrophy of the posterior distal compartment muscles.

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muscular dystrophy (SCARMD) was employed to describe these children, some of whom were later found to be deficient in a 50-kD dystrophin-associated protein, the gene for which was localized to chromosome 13q12, the locus for gamma-sarcoglycan.243,244 Sister proteins were identified,245 and the phenotypes associated with sarcoglycanopathies broadened to include less severely involved children. Before investigating a child for sarcoglycanopathy, primary dystrophinopathy must be excluded. Less than 5% of boys with a Duchenne/Becker phenotype will prove to have a sarcoglycanopathy or other limb-girdle muscular dystrophy, and young girls with a “Duchenne/Becker” phenotype are nearly as likely to be manifesting carriers of a dystrophinopathy as to have an alternative diagnosis.246 Immunostaining of muscle with anti-sarcoglycan antibodies is the standard screening for new cases of sarcoglycanopathy. Muscle biopsies of patients with primary dystrophinopathy will show reduced sarcoglycan immunoreactivity. Therefore, both dystrophin and sarcoglycan immunostaining must be done on the same muscle tissue. Limb-Girdle Muscular Dystrophy 2I: Fukutin-related Protein (FKRP) Deficiency A recently characterized disorder, LGMD2I is one of the most common LGMDs, representing from 11% to 19% of all LGMDs in different series.228,247,248 The disease is caused by a mutation in the FKRP gene on chromosome 19q13.3.249 The most common mutation is a single point (826C>A) missense mutation in one allele (>90%), causing a Leu276Ileu (C826A) change.250 Disease severity correlated with a mutation on the second allele. Age of onset ranges from 0.5 to 27 years, with 61% of patients presenting before age 5 years. These patients present with either a DMD phenotype, caused by heterozygous mutations, or with lateonset limb-girdle syndrome in those with homozygous mutations. The clinical course varies, usually involving weakness and wasting of the shoulder girdle muscles and proximal extremities, with significant calf hypertrophy and elevated serum CK, the increase ranging from 5-fold to 70-fold. Other clinical presentations have been described, including exercise-induced myalgias, isolated myalgias, cramps, and dilated cardiomyopathy with or without muscle weakness.247 In some series, patients presented with muscle pain and myoglobinuria as the earliest presenting symptoms.248 Cardiac and respiratory involvement are relatively common in the heterozygous, earlier presentation cases, occurring in approximately 30% of patients, at times while they are still ambulatory.251,252 Genetic sequencing of the FKRP gene from peripheral blood is commercially available, so diagnosis can be easily confirmed. Muscle biopsy shows characteristic dystrophic changes, with muscle fiber size variation, muscle fiber necrosis and regeneration, and mild increase in connective tissue. The most consistent abnormality is a secondary abnormal laminin-2 immunostaining. Most patients also have a marked decrease in immunostaining of muscle alphadystroglycan and a reduction in its molecular weight on Western blot analysis.249,250 Limb-Girdle Muscular Dystrophy 1A, 2G, and 2J: Sarcomeric Proteins Deficiency Limb-Girdle Muscular Dystrophy 1A (Myotilinopathy) LGMD1A was the first autosomal dominant limb-girdle dystrophy to be linked to a specific gene locus. Initial clinical observations of the co-segregating of two rare diseases in a family with muscular dystrophy and Pelger-Huet anomaly253 and of a family in West

Virginia with proximal weakness and nasal dysarthria254 were followed years later by linkage studies localizing the gene to chromosome 5q31–q33255 and the discovery of the first of several missense mutations in the gene coding for the sarcomeric protein myotilin.256 Myotilin has been implicated in other diseases, including having a causal role in some cases of myofibrillar myopathy257,258 and a secondary role in central core disease and nemaline myopathy.259 The diagnosis in new patients is challenging. Immunostaining of myotilin could be normal. A history of slowly progressive limb-girdle weakness with a family history consistent with autosomal dominant transmission may be obtained, but the incidence of spontaneous mutation is unknown. The findings of heel cord contracture, nasal dysarthria, mild to moderate elevation of CK, and muscle biopsy findings of Z-line streaming and autophagic vacuoles should increase clinical suspicion. Mutation analysis of the myotilin (MYOT) gene is needed for a definitive diagnosis. Limb-Girdle Muscular Dystrophy 2G (Telethonin) Telethonin is a small 19-kD sarcomeric protein expressed in skeletal and cardiac muscle.260 Its gene maps to 17q11–12, and it is seen only in a small cohort of Brazilian families, presenting as a mainly proximal myopathy with onset from ages 9 to 15 years. Muscle biopsy revealed degenerating and regenerating muscle fibers and rimmed vacuoles.261 Future patients can be screened with immunohistochemical techniques using anti-telethonin antibodies. Limb-Girdle Muscular Dystrophy 2J (Titin) Titin is a giant structural sarcomeric protein with a molecular weight of more than 3800 kD. The largest human protein, it forms the third filament system in striated muscle along with actin and myosin. Single titin molecules span half sarcomeres from Z disks to M lines in skeletal and cardiac muscle. Titin contributes to sarcomere assembly and passive tension of myofibrils as well as serving sensor and signaling functions.262,263 Titin serine kinase phosphorylates telethonin, the protein implicated in LGMD2G. Mutations in the titin (TTN) gene on chromosome 2q31 most often produce autosomal dominant tibial muscular dystrophy, a distal muscular dystrophy of mid-adult life with prominent involvement of the tibialis anterior and toe extensor muscles.264 This disorder is most commonly seen in persons of Finnish descent.

Other Distal Muscular Dystrophies A group of dystrophies with predominantly distal involvement that do not fall into the classification of limb-girdle muscular dystrophy are listed in Table 19-2 (pp 363–364) (Fig. 19-11).

Emery-Dreifuss Muscular Dystrophy Both the X-linked and autosomal dominant forms of EmeryDreifuss muscular dystrophy result from mutations in genes coding for nuclear envelope proteins. The X-linked form of Emery-Dreifuss (XL-EDMD or EMD1) is caused by mutations of the EMD gene located at Xq28, which encodes a 34-kD ubiquitously expressed nuclear envelope protein, emerin.265 Approximately 95% of mutations producing XL-EDMD are null mutations associated with a complete absence of emerin in skeletal muscle, as well as smooth muscle, skin fibroblasts, leukocytes, and exfoliative buccal cells. Autosomal dominant Emery-Dreifuss (AD-EDMD or EMD2) and autosomal recessive or sporadic Emery-Dreifuss muscular

Treatment and Management of Muscular Dystrophies

Figure 19-11 A patient with Welander distal myopathy. Notice the distal forearm wasting and wrist drop.

dystrophy (EMD3) result from mutations of the LMNA gene located on 1q21, which encodes two nuclear envelope proteins, lamins A and C.266 Lamin A/C are alternatively spliced products of the same gene and comprise part of the nuclear lamina; they interact with chromatin and other proteins of the inner nuclear membrane, including emerin.267 Mutations of the LMNA gene producing the AD-EDMD phenotype are missense mutations that allow translation of full-length lamin A/C. Immunostaining of lamin A/C is therefore not reliable for confirmation of the diagnosis of AD-EDMD.268 The diagnosis of lamin A/C disorders requires DNA sequencing or mutation scanning.269–271 New mutations have been found to explain the 40% of EMD patients that did not present with the most common emerin or

A

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lamin AC mutations, expanding the genetic heterogeneity of the EMD phenotype. EMD4 and EMD5 decribed in few families are caused by mutations in the synaptic nuclear envelope protein 1 (SYNE1) and 2 (SYNE2). 271a EMD6, caused by mutation in the X-linked four-and-a-half-LIM protein 1 (FHL1) gene, is inherited as an AR or sporadic form.271b Although XL-EDMD and AD-EDMD usually share a similar phenotype, wide clinical variation, with poor genotype-phenotype correlation has been documented in both forms.269,272,273 Interfamilial and intrafamilial phenotypic variability may exist in those sharing identical mutations. The onset of contractures occurs early in the disease in the first or second decade and often precedes clinically significant weakness. Contractures are most prominent at the elbows, Achilles tendons, and posterior cervical muscles (Fig. 19-12A).274 Upper extremity contractures often precede axial and lower extremity deformities. The arms are held in a semi-flexed position. The feet are set in equinus, often with associated toe walking. Posterior cervical contractures preclude full neck flexion (Fig. 19-12B). Contractures usually remain disproportionate to the degree of weakness268 and may be the major factor in functional impairment. Muscle weakness is relatively mild and slowly progressive. The distribution of motor deficits is humeroperoneal with upper extremity (biceps, triceps, and spinal muscles) occurring earlier than leg weakness (tibialis anterior and peroneal muscles). Pseudohypertrophy is not seen and helps clinically differentiate XLEDMD from dystrophinopathy (e.g., Becker muscular dystrophy). Cardiac symptoms may include palpitations, syncope, and diminished exercise tolerance. Supraventricular arrhythmias, atrioventricular conduction block, ventricular arrhythmias, and restrictive or dilated cardiomyopathy may evolve. The risk of ventricular dysfunction and arrythmias is greater in the autosomal dominant than in the X-linked form,275,276 but symptomatic cardiomyopathy may occur in women heterozygous for null emerin mutations. Cardiac symptoms usually evolve after the second decade.

B

Figure 19-12 A, A patient with Emery-Dreifuss muscular dystrophy with diffuse muscle atrophy and prominent contractures. (Reprinted from T. Bertorini, “Muscular Dystrophies” in Pourmand’s Neuromuscular Diseases, Expert Clinicians’ Views, Boston, 2001, Butterworth-Heinemann.) B, A patient with EmeryDreifuss muscular dystrophy, with significant neck extensor contractures limiting neck flexion. (Reprinted from Escolar D: Muscular Dystrophies, in Pediatric Neurology Principles & Practice, Philadelphia, 2006, Mosby.)

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Treatment and Management The management and treatment of LGMDs is in many ways similar to that for DMD, particularly when the disorders present in children. This includes the management of pulmonary complications, contractures, bracing, physical therapy and rehabilitation, and scoliosis surgery when indicated. Several LGMDs affect the heart as well, with management similar to that in DMD, sometimes requiring transplantation. Of particular importance is the management of Emery-Dreifuss muscular dystrophy, in which the severe cardiac complications and prominent contractures necessitate early, aggressive treatment. Specific treatment is not currently available for any of these disorders. In some LGMDs, particularly sarcoglycanopathies, the use of gene therapy may be an option in the future. The small molecular weight of the coding sequences for sarcoglycans makes AAV transfer a feasible approach, and results have been favorable in the rodent model of the disease.277 Actually, in LGMD2D, gene therapy by a local injection restores alpha sarcoglycan and increases muscle fiber size.277a Many of the treatments under investigation for the treatment of DMD may also be of benefit in some of these diseases. Of great interest are drugs or other approaches that might inhibit fibrosis, promote nerve regeneration, or inhibit muscle atrophy. In some cases, the use of steroids has shown some benefit. These drugs have demonstrated a marked benefit in LGMD2L and LGMD2I (fukutin- and FKRP-associated), and some reported benefit in LGMD2D (alpha-sarcoglycan deficient).278,279 In dysferlinopathies, despite the pronounced inflammatory response seen on muscle biopsy, steroids are not beneficial and might worsen the clinical course. Unfortunately, because of the limited number of patients with each particular disease, the performance of randomized, controlled clinical trials similar to those in DMD is difficult. Therefore, decisions regarding the use of steroids in LGMDs should be considered on a case-by-case basis.

involvement of wrist extensors and abdominal muscles. High-frequency hearing loss and retinal vasculopathy (Coats' disease) are additional supportive findings. Exclusion criteria include eyelid ptosis, extraocular muscle weakness, skin rash, elbow contractures, cardiomyopathy, sensory loss, neurogenic changes on muscle biopsy, and myotonia or neurogenic motor unit potentials on needle electromyography. Weakness of the orbicularis oculi is usually asymptomatic but may be appreciated by observing incomplete burying of the eyelashes with forced eyelid closure and the ease with which the closed eyelids can be pried apart. A history of “sleeping with the eyes open” may be offered by a parent or spouse. Facial weakness may not be symmetric (Fig. 19-13). Weakness of scapular fixation is evidenced by scapular winging accentuated by arm elevation in a forward plane (Fig. 19-14). The

Facioscapulohumeral Muscular Dystrophy Facioscapulohumeral muscular dystrophy (FSHD) is inherited as an autosomal dominant disorder with high penetrance and variable expression. From 10% to 30% of cases represent new mutations.280 Prevalence is estimated at 1 in 20,000. FSHD1A is associated with chromosome locus 4q35 and a sequence of repeats named D4Z4.281 Healthy individuals have 11 to 100 repeats on both alleles, whereas patients with FSHD1A have 1 to 10 repeats on one allele.282 An inverse correlation exists between the D4Z4 region size and disease severity,280 with the largest deletions resulting in severe, congenital FSHD.283,284 Commercially available testing of the 4q35 region is the most specific and sensitive diagnostic test for FSHD1A. Subtelomeric translocations between chromosomes 4q35 and 10q26 occur relatively frequently in the general population and may complicate molecular diagnosis. In 5% of FSHD patients, a 4q35 deletion is not identified, suggesting that at least one additional genetic disorder, designated FSHD1B, produces the FSHD phenotype.285 Clinical Features Clinical diagnostic criteria have been established by the FSHD Consortium.286 This group specifies autosomal dominant inheritance, bifacial weakness, and weakness of either the scapular stabilizers or ankle dorsiflexor muscles. Supporting criteria include asymmetry of motor deficits (a finding far more common in FSHD than any other muscular dystrophy); sparing of deltoid, neck flexor, and calf muscles; and

Figure 19-13 A patient with facioscapulohumeral muscular dystrophy with asymmetric facial weakness.

Figure 19-14 A patient with facioscapulohumeral muscular dystrophy, showing wasting of the biceps and the trapezius muscle with prominence of the scapulae protruding upward.

Treatment and Management of Muscular Dystrophies

scapulae ride high on the back, producing the illusion of hypertrophied trapezius muscles. Arm abduction is impaired in the face of normal power and bulk of the deltoid muscles. Wasting of the biceps and triceps with preservation of deltoid and forearm muscles yields a “Popeye” configuration to the arms. Wasting of the clavicular head of the pectoral muscles produces a reversal of the axillary folds with a deep upward slope. Weakness of lower abdominal muscles may result in a pot belly when standing and a positive Beevor's sign (cephalad movement of the umbilicus with neck flexion) when the patient lies supine. Lower extremity weakness is usually first noted in the ankle dorsiflexors with compromised heel walking or overt foot drop. Atrophy is most prominent in the tibialis anterior. Preservation or hypertrophy of the extensor digitorum brevis muscle clinically excludes a neurogenic etiology for the foot drop. Axial paraspinal muscle weakness may result in marked lumbar lordosis, especially in childhood-onset FSHD patients. Congenital onset of FSHD has been associated with mental retardation and epilepsy in children with the largest D4Z4 deletions (EcoRI fragment size of 10kb; .i.e., less than 10 repeats). The congenital-onset, or infantile, phenotype is severe and rapidly progressive, accompanied by sensorineural hearing loss and Coats' disease.287–289 Marked shoulder and pelvic girdle weakness is present before age 6 years with loss of ambulation by age 15 years. The condition may be mistaken for Möbius syndrome. Profound weakness of facial muscles, including extraocular muscles, is typical (Fig. 19-15).

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Diagnosis and Evaluation Results of CK determinations are either normal or slightly elevated; CK levels more than five times laboratory norms suggests an alternative diagnosis. Genetic testing has largely replaced electrodiagnostic and muscle biopsy evaluations in suspect FSHD patients. Electromyography (EMG) studies of moderately weak muscles reveal brief, low-amplitude motor unit action potentials consistent with myopathy; sparse fibrillations reflecting muscle fiber necrosis can also be noted. However, the needle EMG examination may be normal in clinically powerful muscles. Muscle biopsy findings are often nonspecific, with occasional small angular fibers, necrotic fibers, and regenerating “lobulated” fibers. A modest increase in the percent of hypertrophic type II muscle fibers may be seen. Foci of inflammatory cell in a perivascular or endomysial distribution are commonly encountered and on occasion may lead to a pathologic misdiagnosis of polymyositis, particularly in younger patients.290 Treatment and Management Because no proven specific treatments are available for FSHD, the main therapeutic approaches are adaptive and protective. Ankle-foot orthoses for foot drop are commonly utilized. Orthopedic scapular fixation may improve upper extremity function,291,292 but the gain may be short lived. Musculoskeletal and joint pain is common and may require nonsteroidal anti-inflammatory drugs (NSAIDs) or antidepressants if chronic. Routine auditory and ophthalmologic screening is recommended, especially in infantile-onset FSHD, in which Coats' disease is most often seen. Respiratory complications should be kept in mind, and routine measurement of forced vital capacity should be performed on those patients with severe weakness or kyphoscoliosis. Unlike muscular dystrophies associated with sarcolemmal proteins, the muscle fibers in FSHD are not prone to damage as a result of exercise. Multiple studies, in fact, demonstrate beneficial effects of both strength training and aerobic exercise in FSHD.293,294 Care should be taken, however, to avoid injury to weakened joints. The beta-adrenergic agonist albuterol has been shown to improve muscle mass but has little effect on function,295 a finding supported by a study examining the use of both albuterol and strength training.296 Therapeutic trials of corticosteroids have been disappointing.297 Data derived from a trial of creatine that included FSHD patients showed no benefit for this subgroup.145 The clinical trial of the myostatin antibody (MYO-029) discussed in the DMD section of this chapter showed no benefits in function or strength in FSHD either.181 Several strategies are being considered as possible treatment approaches for FSHD in the future. Because patients with FSHD demonstrate hypomethylation in the D4Z4 region, folic acid and vitamin B12 have been evaluated as possible treatments since they contribute to DNA methylation. Initial studies have not shown clear benefit.298 Alternative methods of myostatin inhibition are also being investigated, as is the case in other dystrophic diseases.282 Finally, the autologous delivery of unaffected myoblasts or mesangioblasts is under consideration as a potential approach for therapy.282

Myotonic Dystrophy Figure 19-15 Early onset of infantile form of facioscapulohumeral muscular dystrophy manifests with incomplete eyelid closure and lack of facial expression. (Reprinted with permission from Escolar D: Muscular Dystrophies, in Pediatric Neurology Principles & Practice, Philadelphia, 2006, Mosby.)

Myotonic Dystrophy Type 1 Type 1 myotonic dystrophy (DM1) is an autosomal dominant disorder with multisystem involvement. DM1 is the second most common of the muscular dystrophies, affecting 1 in 8000 individuals.

360 Treatment and Management of Specific Neuromuscular Disorders

It is the most prevalent of the dystrophies in adults. Skeletal, smooth, and cardiac muscles are affected, as well as the eye, endocrine, and central nervous systems. Clinical signs and symptoms are variable, including among affected family members, with a spectrum ranging from asymptomatic to severe. Molecular Genetics Type 1 myotonic dystrophy is caused by a mutation in the length of a CTG trinucleotide repeat in the 30 untranslated region of the myotonic dystrophy protein kinase (DMPK) gene on chromosome 19q. The normal gene has between 5 and 36 CTG trinucleotide repeats. Minimally affected individuals have as few as 50 copies; severely affected DM patients may have thousands of repeats.299 The CTG repeat gene shows marked intergenerational and somatic instability in patients with DM1 when the repeat is expanded to more than approximately 55 repeats.300 Virtually all children with the most severe congenital phenotype have inherited the DMPK allele from their mothers. In fact, the sex of the transmitting parent is an important factor that determines DM allele size in the offspring. The pathophysiologic mechanism of disease in myotonic dystrophy has been recently described as one mediated by “toxic RNA.”301 The repeat expansion of DMPK is actually outside of any coding region, and the protein product is therefore normal. However, the RNA transcript itself (a CUG expanded repeat) is thought to form a hairpin structure that accumulates in the nucleus,302 leading to dysfunction of the RNA binding proteins MBNL1 and CUGBP1.303,304 These proteins normally regulate the alternative splicing of pre-RNA. When this process is misregulated, a “spliceopathy” of the muscle chloride channel and insulin receptor occurs, making abnormal versions of these gene products and leading to the myotonia and insulin resistance seen in DM1.304–306 Cardiac conduction disturbances in DM1 appear to be mediated by mutant RNA increasing the expression of NKX2-5, a cardiac transcription factor.307 Clinical Features The clinical presentation of DM1 is highly variable among patients and within families. Congenital DM1 is most commonly seen in infants born to mothers with DMPK expansion alleles of 600 or more CTG repeats. Symptoms are often noted before birth. Reduced fetal movement and polyhydramnios are warning signs. There is an increased incidence of breech presentation. At delivery, marked hypotonia, generalized weakness, and inefficient respiration are noted. Characteristic facies with a tented upper lip indicating facial diplegia is seen in nearly all infants. Arthrogryposis, most often producing talipes equinovarus deformity, is common. Life-threatening respiratory insufficiency requiring mechanical ventilator support may portend an ominous long-term prognosis. Classic DM1 is most likely to develop in the second to fourth decade (Fig. 19-16) in patients with CTG repeat lengths of 100 or more. Teenagers and young adults may complain of “stiffness” as the first symptom of myotonia. Difficulty with fine motor skills such as handwriting and complaints referrable to distal upper extremity weakness and grip-induced myotonia follow. Evolution of lower limb distal weakness progresses to foot drop and inability to skip or vertically leap. Typical myopathic facies (also described as hatchet facies) with temporal muscle wasting and eyelid ptosis give a “dull” appearance (Fig. 19-17). Nonskeletal muscle signs and symptoms require close clinical attention. Cardiac conduction defects tend to evolve after age 30 years, but early cardiac screening with ECG is needed to detect those patients with progressive atrioventricular conduction block, a significant cause of early death in patients with classic DM1.308

Figure 19-16 An adult patient with myotonic dystrophy. Note wasting of the temples, anterior neck, and forearm muscles.

Figure 19-17 A family with myotonic dystrophy. A mildly affected mother and her two sons with markedly elongated face and temporal wasting.

Smooth muscle dysfunction may produce dysphagia, constipation, or diarrhea. Hypokinesis of the small and large bowel may produce pseudo-obstruction or megacolon. Impaired sphincter of Oddi function predisposes to cholelithiasis. Endocrinopathies, including hyperinsulinism with glucose intolerance and impaired growth hormone secretion, are usually asymptomatic.309 Gonadal atrophy and reduced fertility are common but usually evolve after the prime reproductive years. An underappreciated complication of classic DM1 is hypersomnia, often found in association with both central and obstructive sleep apnea.310 Men may exhibit frontal balding beginning in their late teens. Christmas tree cataracts can be detected with slit-lamp examination beginning in the teens. Women with classic DM1 are at risk for obstetric complications, including

Treatment and Management of Muscular Dystrophies

spontaneous miscarriage; failure of progression of labor, necessitating cesarean section; and postpartum hemorrhage.311 Worsening of motor impairment rarely accompanies pregnancy. All patients with classic DM1 require added precautions when undergoing surgery. Sensitivity to sedatives and inhalation anesthesia mandates close observation in the recovery room. Blunted responses to hypercarbia and hypoxemia may be partially responsible for postanesthetic complications. Diagnosis and Evaluation The universal availability of DNA testing for patients suspected of having DM1 has made other diagnostic investigations obsolete. Lymphocyte DNA assay for the CTG expansion repeat in the DMPK gene is nearly 100% accurate. PCR analysis is performed to detect up to 100 repeats; Southern blot analysis is used to quantitate CTG expansions of greater length. “False negatives” have proven to represent other diseases, most commonly DM2. Older diagnostic techniques for the identification of DM1 are of historical interest. They include needle EMG, which demonstrates waxing and waning high-frequency discharges typical of true myotonia. CK levels are normal or slightly elevated. Muscle biopsy in older children and adults reveals type I muscle fiber atrophy, increased numbers of internal nuclei, and ring fibers. The muscle biopsy in infants with congenital DM1 show poor fiber type differentiation, and peripheral halos of many fibers void of oxidative activity. None of these morphologic findings are pathognomonic for DM1. Myotonic Dystrophy Type 2 (DM2) Shortly after the discovery that myotonic dystrophy was caused by a CTG trinucleotide repeat expansion in the DMPK gene, reports appeared that some patients with typical clinical features of this disorder showed neither the CTG repeat expansion nor localization to 19q13.3.312 Some of these patients manifest weakness in a proximal greater than distal distribution; the term proximal myotonic myopathy (PROMM) was coined to describe this newly appreciated disorder.313,314 Further phenotype-genotype investigations localized the disease to 3q21315 and shortly thereafter the gene was localized to the zinc finger protein 9 (ZNF9) gene and a CCTG repeat sequence expansion in intron 1 of this gene was discovered.316 The toxic accumulation of RNA theory described above also applies to the CCTG transcript of this repeat.316 These manifest both proximal motor deficits as well as findings typical for classic myotonic dystrophy. The majority of patients with DM2 present in their adult years, but patients as young as age 8 years have demonstrated symptoms. Importantly, no congenital phenotype has yet been reported.317,318 DM1 and DM2 share common findings of myotonia, early cataracts, frontal balding, and cardiac involvement. DNA studies provide the means for definitive classification of affected patients. Treatment and Management Patients diagnosed with myotonic dystrophy require education about their disease and an explanation of the phenomenon of anticipation (especially for young women of child-bearing age). Periodic pulmonary function studies and ECGs should begin in the second decade and cardiology consultation obtained liberally throughout the lives of these patients for symptoms suggestive of arrhythmias, syncope or presyncope, or progressive ECG changes. Routine ophthalmologic examination is recommended to screen for cataracts.

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Myotonia is not the most serious complication of DM, although it can exacerbate disability. Trials of drugs such as phenytoin (100 mg two to three times per day), carbamazepine (600 to 800 mg/day), or mexiletine (150 to 200 mg three times per day) may be helpful for treatment of myotonia in selected patients, but their safety and efficacy have not been studied in long-term randomized, controlled trials.319 These are all sodium channel blockers, and their use could exacerbate weakness in these patients. Furthermore, mexiletine should be avoided in patients with second- and third-degree heart block, which are not uncommon in these diseases. Muscle pain is a common complaint in patients with DM2 and may respond to NSAIDs, gabapentin, or tricyclic antidepressants. Lethargy and fatigue may suggest central or obstructive sleep apnea. If sleep studies are negative, empiric trials of stimulant medications may be helpful for these symptoms. Patients undergoing surgery should make both surgeon and anesthesiologist aware of their neuromuscular disorder, limit the use of sedative agents, and anticipate a prolonged period of observation in the recovery room. Ankle-foot orthoses help address distal lower limb weakness and foot drop. Lesser degrees of distal leg weakness can be helped by well-supported, high-topped athletic shoes. At later stages, the use of walkers or wheelchairs may become necessary. The infant with congenital DM1 requires a multidisciplinary approach with occupational, physical, and speech therapy services. Nutritional consultation and trials of various food consistencies are often helpful. Parents and teachers should anticipate cognitive impairment and learning disabilities and monitor for symptoms of attention deficit disorder. Future Targets for Specific Treatment in Myotonic Dystrophy

Because of the presumed causative nature of mutant RNA in myotonic dystrophy, this and the mechanisms affected by it are appealing targets for therapy. The most direct approach would be elimination of the mutant RNA itself. Approaches using either ribozyme or antisense RNAs designed to degrade mutant DMPK alleles have shown some promise in myoblasts.320,321 A study on murine models demonstrated that exon skipping with antisense oligonucleotides could achieve normal chloride channels with improvement of myotonia.322 Other approaches of interest are manipulation of the expression of the RNA binding proteins MBNL1 and CUGBP1, which are affected by the accumulation of the mutant RNA.323 The progressive muscle wasting in DM1 appears to be secondary to a defect in muscle anabolism.324,325 This has led to the study of anabolic agents as possible treatments for the disease. Testosterone326 and creatinine327,328 have not shown any benefit. Dehydroepiandrosterone (DHEA) has been shown to improve strength in a small pilot study.329 Studies of compounds including recombinant human insulin-like growth factor, a strong stimulator of anabolism, are currently underway.323

Oculopharyngeal Muscular Dystrophy Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, adult-onset disease. The gene has been mapped to chromosome 14q11.2-q13, and the disease is caused by a trinucleotide repeat (GCG) expansion. This repeat occurs in the coding region of the polyalanine binding protein-nuclear 1 (PABPN1) gene. Histopathology demonstrates small angulated fibers, rimmed vacuoles in muscle fibers, and intranuclear inclusions consisting of mutated aggregates of PABPN1.330

362 Treatment and Management of Specific Neuromuscular Disorders

OPMD typically presents after age 50 years.331 Many affected individuals of French Canadian descent are traced to a single ancestor from France,332 although it can also occur in other ethnic groups. OPMD is recognized in the fourth to sixth decade by onset of ptosis, partial extraocular muscle paresis, dysphagia, and tongue weakness. Proximal upper and lower extremity muscle weakness (see Fig. 1-5D) slowly develops. Serum CK level may be normal or mildly elevated. Progressive oculopharyngeal dysfunction was described in Greek siblings, ages 11 and 14 years, who both had rimmed vacuoles; one had cytoplasmic and intranuclear tubulofilamentous inclusions 25 nm in diameter on muscle biopsy.333 Another childhood-onset oculopharyngeal syndrome presented with intestinal pseudo-obstruction.334 These may be examples of recessively inherited conditions similar to dominantly inherited OPMD. Treatment and Management Several specific therapies are under investigation in OPMD cells and in animal models of OPMD. Trehalose is a disaccharide chemical chaperone that has been shown to decrease PABPN1 aggregates and improve muscle weakness.335 Antibodies to different epitopes of PABPN1 have been identified that, when expressed intracellularly, can prevent and reduce aggregations of PABPN1.336 Doxycycline has been shown to delay and lessen the severity of symptoms in a murine model as well as reduce PABPN1 aggregates.337 A human trial is underway that will examine the utility of autologous satellite cell therapy in OPMD.338 Due to the unavailability of specific therapies, adaptive measures are of most benefit currently for OPMD patients. These include the treatment of ptosis either surgically or with eyelid crutches. For diplopia, Fresnel prisms might be helpful in some patients. Speech therapy consultation and close monitoring of swallowing function are also important.

Congenital Muscular Dystrophy The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders characterized by hypotonia, weakness, and variable degrees of muscle contractures. They are normally classified into syndromic (with brain and eye abnormalities) and nonsyndromic types. Within these broad classifications considerable phenotypic variation exists, and clinical differences may be more quantitative than qualitative. However, evidence supports genetically distinct bases for the different CMD subgroups. The summed incidence of all forms of CMD is approximately 1 in 21,500.339 Signs and symptoms are evident in the newborn period or the first few months of life. Serum CK is usually elevated. Muscle biopsy abnormalities suggesting a myopathic or dystrophic process, including variation in muscle fiber size, necrotic and regenerating fibers, and an increase in endomysial connective tissue, establish a working diagnosis of CMD. Delineation of a precise diagnosis requires integration of muscle and systemic findings, immunostaining or Western blot of extracellular proteins, and DNA testing when available. Nonsyndromic Congenital Muscular Dystrophies The most common of the nonsyndromic types is merosin-negative congenital muscular dystrophy (MDC1A). Merosin is the heavy a2 chain of laminin-2 (LAMA2). The laminins are heterotrimeric proteins that influence cell adhesion, growth, and migration. LAMA2 is expressed in the basement membrane of muscle fibers, Schwann cells of intramuscular nerves, and at neuromuscular

junctions. LAMA2 promotes myotube stability and inhibits apoptosis.340 Patients with complete absence of merosin present as hypotonic infants with limb weakness, normally more prominent than bulbar or respiratory impairment, and multiple joint contractures (Fig. 19-18A). On magnetic resonance imaging, white matter abnormalities, seen as increased signal on T2-weighted images, involve the centrum semiovale.341 Epilepsy occurs frequently, even in patients with normal intellect.342 Absence of immunohistochemical staining for the laminin a2 chain on snap frozen muscle biopsy tissue provides confirmation of the diagnosis of merosin deficiency (Fig. 19-18B). Prenatal diagnosis of merosin-deficient CMD is possible by direct mutation analysis of chorionic villus biopsy material or linkage analysis. Direct immunostaining of trophoblasts from chorionic villus samples with laminin a2 chain antibodies provides an additional method for prenatal diagnosis. Another nonsyndromic CMD is the merosin-positive group (MDC1B). The majority of patients with normal merosin expression or partial merosin deficiency presenting with a CMD phenotype have other genetic disorders that do not link to 6q. They share a similar, but usually milder clinical course than merosin-negative children. CMD due to FKRP deficiency (MDC1C) usually presents at birth or in the first few weeks of life with hypotonia and leg muscle hypertrophy. CK values are greatly increased (1000 to 10,000 IU/ L). Children follow a regressive course that may include cardiomyopathy. Immunohistochemical staining reveals partial merosin deficiency and severely reduced alpha-dystroglycan. The reduced molecular weight of alpha-dystroglycan on Western blot indicates that defective glycosylation is important in the pathophysiology of MDC1C. The genetic defect maps to 19q13.3, and DNA testing is commercially available. CMD with integrin a-7 deficiency is a rare disorder that has been discovered in the analysis of large groups of patients with undefined congenital myopathies. The muscle biopsies of three patients showed deficiency of this protein with different mutations in the ITGA7 gene on chromosome 12q13.343 CMD with early rigid spine syndrome is another rare form seen in consanguineous Moroccan, Turkish, and Iranian families that demonstrate mutations in the gene on chromosome 1p35–46 coding for selenoprotein.344 An American family has also been described demonstrating a phenotype of infantile hypotonia, cervical muscle weakness, and early spinal rigidity with scoliosis that maps to the same locus on 1p.345 Ullrich CMD is caused by autosomal recessive mutations in any of three genes encoding collagen VI, an extracellular matrix protein.346,347 The protein is composed of three alpha peptide chains, which are encoded by two genes on chromosome 21q22.3 and one gene on chromosome 2q37. The disease presents with infantile weakness, hypotonia, and early severe proximal joint contractures with hyperlaxity of distal joints.348 The distal laxity may be replaced by progressive flexion contractures of the wrists, fingers, and ankle. Serum CK is usually normal or only slightly elevated. Muscle biopsy shows nonspecific myopathic or dystrophic changes with reduced or absent collagen VI immunostaining.349 Bethlem myopathy, also due to mutations in collagen VI genes, was first described as a benign myopathy with autosomal dominant inheritance.350 Clinical features are much more variable than in Ullrich CMD. Patients usually have proximal weakness in early childhood and may demonstrate the Gowers sign. More severe cases may present in neonates with hypotonia, foot deformities, torticollis, and arthogryposis. Unlike Ullrich CMD, weakness is usually nonprogressive, but contractures may develop late in the first decade in the ankles, elbow flexors, and finger flexors.

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363

A

B

C

D

Figure 19-18 A, A patient with merosin-deficient congenital muscular dystrophy. The patient has a tracheotomy, prominent contractures, and scoliosis. B, Muscle biopsy from the same patient stained modified with trichrome. Note the fiber atrophy, increased endomysial connective tissue, and fat (400). C, Note the lack of merosin compared with a normal control (D). (A, Reprinted with permission from Bertorini T: Neuromuscular Case Studies, Philadelphia, 2008, Butterworth-Heinemann.)

Table 19-2 Distal Muscular Dystrophies

Type and Eponym Late adult-onset, predominantly in hands (Welander) (AD)

Gene Localization

Gene Product

Initial Weakness

2p13

Unknown

Hands: finger/wrist extensors

Normal or slightly elevated

Myopathic: vacuoles in most cases

Titin

Legs; anterior compartment

ZASP

Legs: anterior compartment

Normal or slightly elevated Normal or slightly elevated

Vacuolar myopathy, sarcolemmal disruption, accumulation of myofibrillar proteins As above but fewer vacuoles

Increased, usually <5 normal

Vacuolar myopathy

Late adult-onset, predominantly in legs IIa. Finnish (Tibial, Udd) (AD) 2q31

IIb. Markesbery-Griggs* (AD) 10q22.3-23.2

Serum CK Level

Biopsy

Early adult-onset, anterior 9p1q1 compartment in legs (Nonaka type, quadriceps-sparing, HIBM2) (AR; some sporadic)

GNE: glucosamine Legs: anterior (UDP-N-acetyl)compartment 2-epimerase/ N-acetylmannosamine kinase

HIBM with Paget disease and frontotemporal dementia (AD)

9p13-p12

Valosin-containing protein (VC)

Legs: mainly anterior Normal or compartment slightly elevated

Vacuolar myopathy

HIBM-3 (AD)

17p13-1

MyHC-IIa: type IIa myosin heavy chain

Variable presentation

Vacuolar myopathy

Normal in children, elevated in adults

Continued

364 Treatment and Management of Specific Neuromuscular Disorders Table 19-2 Distal Muscular Dystrophies—Cont’d

Type and Eponym

Gene Localization

Gene Product

Initial Weakness

Serum CK Level

Biopsy

Early adult-onset posterior compartment in legs (Miyoshi) (AR)

2p13

Dysferlin (allelic to LGMD 2B)

Legs: posterior compartment

Increased, 10–150 normal

Myopathic, necrosis, no vacuoles; dysferlin deficiency

Early adult-onset (Laing) (AR)

14q11

Myosin heavy chain 7

Legs: anterior compartment; neck flexors

Slightly increased, <3 normal

Moderate myopathic changes; no vacuoles

Distal myopathy with vocal cord and pharyngeal weakness (onset in fourth to sixth decades) (AR)

5q31

Matrin 3

Legs: anterior compartment; finger extensors may first be involved

Normal to moderately increased

Vacuolar myopathy

Myofibrillar myopathy (AD, spororadic) (onset in childhood to fifth decade)

2q35 (AP.AR) 11q21-23 (AD) 5q22.3-3.13(AR) 10q22.3-23.2(AD) 7q32.1(AD) 1p36 (AR)

Desmin Crystallin aB CAP myotilin ZASP Filamin C Selenoprotein N1

Hands or legs, some Moderately increased, with <5 normal scapuloperoneal

Myopathic, usually with vacuoles; subsarcolemmal granules or cytoplasmic bodies; accumulation of desmin and other myofibrillar proteins

3p25 (AD)

Caveolin

2q (AR)

Nebulin

Variable Elevated presentation Young adults; tibial Normal and facial weakness

Dystrophic changes, caveolin deficiency Some small nemaline rods

Others Some caveolinopathies Nebulin gene mutations *

This should be considered a myofibrillar myopathy. AD, autosomal dominant; AR, autosomal recessive; HIBM, hereditary inclusion body myopathy; MyHC, myosin heavy chain; ZASP, Z-band alternatively spliced PDZ motif-containing protein.

Syndromic Congenital Muscular Dystrophies A summary of the syndromic congenital muscular dystrophies (Fukuyama congenital muscular dystrophy, muscle-eye-brain disease, and Walker-Warburg syndrome) is shown in Table 19-1. These are three clinically defined CMDs with associated brain malformations. They involve the brain because the genes and protein products of these disorders are involved in glycosylation of both extracellular muscle and brain protein. The treatment of CMDs is mostly symptomatic, and these approaches are discussed in Chapter 12. There is preclinical evidence that merosin-negative CMD can respond to costicosteroid treatment.351 This has also been shown in patients with CMD 1A followed by one of the authors (DE). These patients clearly respond to prednisone at a dose similar to that used for DMD treatment, with increase in muscle strength and function sustained over many years. Thus, a trial of corticosteroid treatment in this form of CMD should be considered. References 1. Emery AE: The muscular dystrophies, Lancet 359(9307):687–695, 2002. 2. Baumbach LL, Chamberlain JS, Ward PA, et al: Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies, Neurology 39(4):465–474, 1989. 3. Burmeister M, Lehrach H: Long-range restriction map around the Duchenne muscular dystrophy gene, Nature 324(6097):582–585, 1986. 4. Gillard EF, Chamberlain JS, Murphy EG, et al: Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene, Am J Hum Genet 45(4): 507–520, 1989. 5. Hoffman EP, Fischbeck KH, Brown RH, et al: Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy, N Engl J Med 318(21):1363–1368, 1988.

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