Part 25: Muscle Chapter 216: The Muscular Dystrophies

Chapter 216: The Muscular Dystrophies
PART 25: MUSCLE

Peter B. Kang, Louis M. Kunkel
Abstract
1. The muscular dystrophies are a broad class of primary muscle disorders with a diverse range of
genetic etiologies, clinical presentations, and natural history. The disease generally arises through a
loss of function of the affected protein product. They share a common histopathologic picture of
muscle degeneration and regeneration, characterized by fiber necrosis, inflammation, and
fibroadipose replacement of muscle fibers. This distinguishes them from the congenital myopathies,
which are associated with muscle fiber dysmorphology, often due to abnormal accumulations of
various proteins.
2. The first description of Duchenne muscular dystrophy (DMD) (OMIM 310200), the most common
form, is generally attributed to Duchenne de Boulogne in 1861, although there are several reports
published earlier in the nineteenth century by Edward Meryon and others that appear to present the
same disease. A major milestone in the genetics of this disorder came in 1986, when the gene
causing DMD was cloned. A year later, its protein product, dystrophin, was identified. Since then,
several dozen genes have been associated with various forms of muscular dystrophy (gene
sequences available at http://www.dmd.nl/).
3. The complexities of the genotype-phenotype correlations in the muscular dystrophies make it difficult
to classify them. Two different schemas are presented, one organized by categories of the various
proteins encoded by the causative genes, the other organized by phenotype. The former will be more
useful for scientific researchers, the latter for clinicians.
4. In a phenotypic classification, the X-linked dystrophinopathies DMD and Becker muscular dystrophy
(BMD) (OMIM 300376) are the most common forms of muscular dystrophy. Both are caused by
mutations in the gene DMD (also known as dystrophin). The classic form of BMD has a milder
phenotype than DMD, but the boundary between the two phenotypes is not always easy to
determine, as there is a spectrum of clinical manifestations.
5. The autosomal dominant limb girdle muscular dystrophies (LGMDs) are to some extent
phenotypically similar to the milder forms of dystrophinopathy. There are three autosomal dominant
LGMDs for which causative genes have been identified. LGMD1A (myotilinopathy) (OMIM 159000) is
caused by mutations in TTID. Mutations in LMNA cause a variety of phenotypes, including LGMD1B
(laminopathy) (OMIM 159001), Emery-Dreifuss muscular dystrophy (OMIM 310300, 181350,
604929), cardiomyopathy, lipodystrophy, and Hutchinson-Gilford progeria. LGMD1C is also known as
caveolinopathy (OMIM 607801) and is caused by mutations in CAV3. There are three other forms of
autosomal dominant LGMD for which causative genes have not yet been identified: LGMD1D,
LGMD1E, and LGMD1F.
6. The autosomal recessive LGMDs tend to be more severe, and have some phenotypic similarities to
the more severe end of dystrophinopathy spectrum. They include LGMD2A (calpainopathy; CAPN)
(OMIM 253600), LGMD2B (dysferlinopathy; DYSF) (OMIM 253601), LGMD2C (-sarcoglycanopathy;
SGCG) (OMIM 253700), LGMD2D (-sarcoglycanopathy; SGCA) (OMIM 608099), LGMD2E
(-sarcoglycanopathy; SGCB) (OMIM 604286), LGMD2F (-sarcoglycanopathy; SGCD) (OMIM
601287), LGMD2G (telethoninopathy; TCAP) (OMIM 601954), LGMD2H (TRIM32) (OMIM 254110),
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LGMD2I (FKRP) (OMIM 607155), LGMD2J (TTN) (OMIM 608807), and LGMD2K (POMT1) (OMIM
609308).
Congenital muscular dystrophies form a third category of muscular dystrophies after the
dystrophinopathies and the LGMDs. They include milder phenotypes such as Ullrich disease
(COL6A1, COL6A2, COL6A3) (OMIM 254090) and rigid spine syndrome (SEPN1) (OMIM 602771).
The most common congenital muscular dystrophy, traditionally referred to as merosin deficiency (MDC1A;
LAMA2) (OMIM 607855), has a moderately severe phenotype. A mutation in FKRP may cause a
moderate form of congenital muscular dystrophy (MDC1C) (OMIM 606612) as well as LGMD2I. The three
classic severe congenital muscular dystrophies are Fukuyama congenital muscular dystrophy
(FCMD) (OMIM 253800), muscle-eye-brain disease (POMGnT1) (OMIM 253280), and
Walker-Warburg syndrome (POMT1, FCMD, FKRP) (OMIM 236670).
Some distal myopathies have dystrophic features on histology, including Miyoshi myopathy (DYSF)
(OMIM 254130), which is allelic to LGMD2B; and tibial muscular dystrophy (Udd myopathy; TTN)
(OMIM 600334), which is allelic to LGMD2J.
Several unique phenotypes do not easily fit into one of the above categories, including Bethlem
myopathy (COL6A1, COL6A2, COL6A3) (OMIM 158810), Emery-Dreifuss muscular dystrophy (EMD,
LMNA) (OMIM 310300, 181350, 604929), facioscapulohumeral muscular dystrophy (OMIM 158900),
and oculopharyngeal muscular dystrophy (PABP2) (OMIM 164300).
The natural history ranges widely in these disorders, from the most severe congenital muscular
dystrophies that are rapidly fatal to very mild diseases that have onset in adulthood and do not cause
significant disabilities. Other organ systems may be involved, depending on the specific disease, including
the heart, lungs, spine, eyes, and brain. In the more severe forms, the usual cause of death is a cardiac or
pulmonary complication.
The protein products of the genes known to cause muscular dystrophy perform a variety of functions
and are clustered in several specific locations within or outside the muscle fiber. One cluster forms the
dystrophin-associated protein complex (DAPC), which is linked to a second cluster in the extracellular
matrix complex through sarcolemmal proteins. Three other clusters lie in the sarcomere, Golgi apparatus,
and nucleus. There are a few proteins that do not easily fall into these five main categories, such as
enzymes. The functions range from structural to signaling to glycosylation, depending on the specific
protein. Many of these proteins are also expressed in nonmuscle tissues, often leading to multiorgan
involvement in the muscular dystrophies.
The diagnosis of the muscular dystrophies has changed dramatically since the gene for DMD was
cloned in 1986. Many children with DMD and BMD no longer require uncomfortable and invasive
diagnostic tests such as electromyography and muscle biopsy. In about two-thirds of cases, deletion and
duplication analyses on DNA obtained from blood lymphocytes suffice to confirm the diagnosis after an
elevated creatine kinase (CK) level has been documented. Muscle biopsy may still be required in
many of the remaining cases, as well as in many of the other forms of muscular dystrophy, although
mutation analysis is increasingly being used to confirm the diagnosis.
Many of the genes that cause the muscular dystrophies have homologues in other organisms. Three
organisms that are commonly used as models of muscular dystrophy are the mouse, dog, and zebrafish.
The mdx mouse is the most widely used model. The xmd dog more closely replicates humans in
general and DMD in particular compared with the mdx mouse, but is a more difficult organism to work
with. Zebrafish models of muscular dystrophy have recently been developed and show promise in certain
settings due to their rapid reproductive cycle.
Significant progress has been made in the therapy of the muscular dystrophies over the past two
decades. Steroid therapy prolongs ambulation in DMD. Surgery for scoliosis alleviates the respiratory
complications and makes the patient more comfortable. The development of portable respirators has
preserved motility late in the course even when respiratory failure occurs. Angiotensin-converting
enzyme (ACE) inhibitors improve the course of cardiomyopathy, which complicates DMD, BMD, and
other muscular dystrophies. Physical and occupational therapy also have been helpful. The life
expectancy and quality of life have both improved significantly for affected individuals. A definitive cure,
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however, remains elusive. A new generation of potential therapies has emerged from the laboratory, and
hope remains that one of these will eventually develop into a cure.
Background
History
Several works of art dating as far back as ancient Egypt, as well as some medieval paintings, are
suspected of portraying undiagnosed cases of muscular dystrophy (Emery, 1995). In the nineteenth
century, Sir Charles Bell, Gaetano Conte, Richard Partridge, William Little, and Edward Meryon all
published descriptions of what most likely were cases of muscular dystrophy (Emery, 1995; Little, 1953;
Meryon, 1852; Tyler, 2003). These descriptions were not, however, recognized at the times of publication
as representing a distinct disease.
Guillaume Benjamin Amand Duchenne de Boulogne, a French physician, published a description of his
eponymous disorder in 1861 (Duchenne, 1861). His first case was that of a 9-year-old boy who began
walking at 18 months. The patient had difficulty walking and getting up after falling, and had equinovarus
deformity. Duchenne noted pseudohypertrophy of the calves and mental retardation. He studied this
disorder in more detail and described a number of other cases, thus leading to its recognition as a disease
entity (Duchenne, 1868).
William Gowers defined the natural history in great detail and described what is now known as the Gowers
sign (Gowers, 1879). He noted the onset before age 6, loss of ambulation at 10 to 12 years, and death by
14 to 18 years (Emery, 1995). Additionally, he accurately described the patterns of muscle weakness,
wasting, and pseudohypertrophy.
Facioscapulohumeral muscular dystrophy was described later in the nineteenth century. For most of the
twentieth century, advances were restricted to descriptions of other forms of muscular dystrophy, including
BMD (Becker, 1953), limb girdle muscular dystrophy (LGMD), Emery-Dreifuss muscular dystrophy,
oculopharyngeal muscular dystrophies, and congenital muscular dystrophies.
The modern history of the muscular dystrophies began in the 1980s (Kunkel, 2005). The hunt for the gene
responsible for DMD had one important advantage and one important handicap. The advantage was that
the X-linked inheritance limited the search to the X chromosome. The handicap was that the biochemical
defect was also unknown. This great intellectual effort by many groups around the world was conducted at
a time when the polymerase chain reaction (PCR) was in its infancy and DNA sequencing was a laborious
process involving copious use of radioactive markers rather than the fluorescent ones involved in current
automated DNA sequencers.
The first step was the creation of a recombinant DNA library for the X chromosome. Chromosomes were
isolated from cell lines obtained from patients with 48, XXXX (Davies et al, 1981) and 49, XXXXY (Kunkel
et al, 1982) aneuploidy. The X chromosomes were sorted from the other chromosomes based on their
prominent fluorescence peaks on flow cytometry. After restriction endonuclease digestion, the resulting
DNA fragments were cloned into phage libraries.
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The gene was localized to the short arm of the X chromosome using two independent approaches:
linkage analysis of restriction fragment length polymorphisms in patients with DMD (Davies et al, 1983;
Murray et al, 1982) and BMD (Brown et al, 1985; Kingston et al, 1984); and mapping of X-autosome
reciprocal translocations in girls with DMD (Boyd et al, 1986; Verellen-Dumoulin et al, 1984). The former
led the way to accurate prenatal diagnosis of DMD, even though the responsible gene had yet to be
identified (Bakker et al, 1985). One of the X-autosome reciprocal translocation cases involved the transfer
of part of a ribosomal DNA repeat unit from chromosome 21 to the X chromosome, creating a site on the
X chromosome near the DMD gene that could be explored with rDNA probes (Worton et al, 1984).
Intense investigation of another unusual patient, B.B., also was underway by several groups. This boy had
four X-linked disorders: DMD, retinitis pigmentosa, chronic granulomatous disease, and the rare red-cell
phenotype McLeod. Karyotyping suggested a deletion in the Xp21 region of the X chromosome, while
Southern blot analysis of his DNA demonstrated a lack of hybridization of the 754 probe, confirming the
deletion and also excluding the possibility that the missing DNA had been translocated to an autosome
(Francke et al, 1985).
Further characterization of B.B.s deletion was accomplished using a hybridization method called
phenol-enhanced reassociation technique (PERT). A small amount of DNA isolated from a 48, XXXX
individual was cleaved with MboI, leaving ends compatible with cloning into BamH1 sites. These cleaved
control samples were then mixed with a much larger amount of B.B.s DNA, which had been sheared to
create blunt ends. Thus, only those restriction fragments from the control DNA that could not hybridize to
B.B.s DNA would self-hybridize and be able to insert themselves into a vector cleaved with BamH1.
There were 125 clones isolated in all, but only 4 were confirmed to be absent in B.B.s DNA by Southern
blot analysis; they were named pERT55, pERT145, pERT84, and pERT87 (Kunkel et al, 1985). Another
set of clones was isolated using the rDNA probes mentioned above (Ray et al, 1985).
One clone from each group failed to hybridize with the DNA of a subset of DMD and BMD patients,
suggesting that these clones corresponded to parts of the causative gene. These clones were named
DXS164 (pERT87) (Kunkel, 1986; Monaco et al, 1985) and DXS206 (XJ-1.1) (Ray et al, 1985).
Chromosome walking was used to isolate large blocks of DNA surrounding the original deletion-detecting
clones and exons identified by sequence conservation. Similar chromosome walks were undertaken at the
DXS206 (XJ-1.1) locus and again sequence conservation used to identify putative exons. One of these
putative exons hybridized to a large RNA species obtained from human fetal skeletal muscle. This
fragment was used to isolate cDNA clones representing at least eight small regions, presumably exons, in
the DXS164 locus (Monaco et al, 1986). These turned out to be the first exons sequenced for the gene
deficient in DMD. This was soon followed by another clone containing further independent exons of a
possibly very large gene (Burghes et al, 1987).
Subsequently, the complete sequence of the predicted protein product of the DMD gene at Xp21 was
obtained (Koenig et al, 1987) and the protein product identified and named dystrophin (Hoffman et al,
1987). Dystrophin was then localized to the subsarcolemmal region (Arahata et al, 1988; Bonilla et al,
1988; Watkins et al, 1988; Zubrzycka-Gaarn et al, 1988). In the two decades since these discoveries,
several dozen other genes associated with less common forms of muscular dystrophy have been cloned
(Fig. 216-1). Further details about these specific genes and their protein products are provided below. The
diagnostic evaluation of children with muscular dystrophy has been revolutionized as a result.
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The development of knowledge of muscle fiber structure over time, including the dystrophin-associated
protein complex. A, Muscle fiber structure before the 1980s. B, The late 1980s to early 1990s, when
dystrophin and the dystroglycans were characterized. C, By the mid-1990s, the sarcoglycan complex and
several further proteins were identified. D, By the late 1990s, dysferlin and caveolin were identified, as
well as fukutin in the Golgi compl...
Classification
The muscular dystrophies are most commonly classified phenotypically (Table 216-1). However, when
thinking about the muscular dystrophies on a molecular level, it is most useful to categorize them by the
cellular location of the encoded protein in relation to the muscle fiber (Table 216-2). The clinical
presentation and natural history section will be organized according to the categories listed in Table
216-1, while the genetics and biochemistry section will be organized according to the listings in Table
216-2.
Table 216-1: Phenotypic Classification of the Muscular Dystrophies
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Clinical Form
Abbreviation
inheritance
Key Features
Duchenne (OMIM No.

310200)
DMD
X-linked
Severe, progressive muscle

degeneration, onset ages 46, loss of
ambulation at ages 912, death at ages
1420 of respiratory
failure/cardiomyopathy
Becker (OMIM No.

310200)
BMD
X-linked
Mild form, onset after age 16, muscle

pain, dilated cardiomyopathy may
require heart transplant
Limb-Girdle (OMIM: see

Table 216-2)
LGMD
AD or AR
Severity variable, overlap DMD and

BMD, involves primarily shoulder and
pelvic girdle muscles
Congenital (classic)
(OMIM 156225)
CMD
AR
Hypotonia, joint contractures, general

muscle weakness, many never become
ambulatory
Congential (Fukuyama)
(OMIM 253800)
FMD
AR
Common only in Japan, similar to

classic form but severe mental
impairment, CNS alterations
Emery-Dreifuss, (OMIM
310300)
EDMD
X-linked
Contractures of elbow, neck, and spine,

scapulohumeroperoneal weakness,
cardiac conduction defect
Oculopharyngeal (OMIM:
see Table 216-2)
OPMG
AD or AR
Eyelid ptosis and dysphagia, onset after

age 50,
Fascioscapulohumeral
(OMIM, 158900)
FSHMD
AD
Facial and shoulder weakness, scapular

winging, variable cardiac involvement
NOTE: AR = autosomal recessive; AD = autosomal dominant.
Table 216-2: Cellular Localization of Proteins Involved in the Muscular Dystrophies
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Disease
Chromosome
Location
Defective
Protein
OMIM
Genbank
Accession No.
DMD
Xp21
Dystrophin
310200
NM000109
BMD
Xp21
Dystrophin
310200
NM000109
XLDC
Xp21
Dystrophin
310200
NM000109
LGMD-1A
5q22-34
Unknown
159000
LGMD-1B
1q11-21
Unknown
159001
LGMD-1C
3p25
Caveolin-3
601253
NM001234
LGMD-2A (Amish)
15q15-21
Calpain-3
253600
AF127765
114240
LGMD-2B/Mioshi
myopathy
2p13
Dysferlin
253601
NM003494
603009
LGMD-2C/SCARMD
13q12
-Sarcoglycan
253700
NM000231
LGMD-2D/ARMD
17q12-21
-Sarcoglycan
600119
NM000023
LGMD-2E
(Amish)/ARMD
4q12
-Sarcoglycan
600900
NM000232
LGMD-2F
5q33-34
-Sarcoglycan
601287
NM000337
601411
LGMD-2G
17q11-12
Unknown
601954
LGMD-2H (Hutterite)
9q31-34
Unknown
254110
CMD, classic
6q2
Merosin
156225
AI636560
CMD, Fukuyama
9q31-33
Fukutin
253800
AB008226
EDMD
Xq28
Emerin
310300
NM000117
OPMD
4q11-13
PABP2
164300
NM004643
257950
FSHMD
4q
Tandem repeat
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158900
Clinical Presentation and Natural History: Dystrophinopathies

Duchenne Muscular Dystrophy
The original descriptions of DMD as published by Meryon, Duchenne, Gowers, and their peers in the
nineteenth century remain unmatched. Nearly all affected individuals are male due to the X-linked
recessive inheritance; rare female patients are seen in cases of X-autosomal translocations. The onset of
symptoms is typically between the ages of 3 and 5 years, although some variation exists. In retrospect,
some parents recall slightly delayed early motor milestones, typically not significant enough to warrant
evaluation. The initial presenting symptoms may include frequent tripping and falling, toe-walking,
waddling gait, or vague complaints of difficulty walking. Occasionally an affected child is identified as a
result of complications of anesthesia, including cardiac arrest and rhabdomyolysis (Farrell, 1994; Larsen
et al, 1989).
The overall incidence has been estimated to be 1 in 3300 live male births. DMD is found throughout the
world and shows no geographic or ethnic predisposition.
The physical examination is notable for proximal motor weakness, most prominently at the hip girdle
muscles. Confrontation muscle strength testing is not always possible at this age, especially if there are
cognitive delays as well. Thus, the most reliable means of assessing proximal muscle strength remains
the Gowers sign, described in the late nineteenth century. The child is asked to rise from a sitting or lying
position to a standing position. A child with hip extensor weakness as is found in DMD will not be able to
rise directly to a standing position. In a classic Gowers sign, an affected child will compensate for weak
hip extensor muscles by raising the hips in the air first with legs extended, then "crawl" up the legs with
the hands to elevate the trunk. There are variations on this maneuver that may be used depending on the
extent of weakness and the personal preference of the child, but the constant finding is the elevation of
the hips higher than the head at some point during the maneuver. These other maneuvers are often
referred to as "modified Gowers signs."
An older child or a particularly cooperative younger one will be able to comply with confrontation testing,
demonstrating a predominantly proximal symmetrical pattern of weakness early in the course, with spread
to more distal muscles in later years. The legs are typically weaker than the arms. There are other,
somewhat puzzling patterns of weakness. The tibialis anterior, which controls dorsiflexion (upward
movement) of the foot, is affected earlier and more severely than the gastrocnemius and soleus, which
control plantarflexion (downward movement) of the foot. However, both are large calf muscles. There is no
immediate explanation for these patterns, which are consistently found in children with DMD.
The other major physical sign evident early in the course is muscle pseudohypertrophy, which is typically
most noticeable in the calves. However, it can be present in other muscles as well. The enlargement of
the muscles is referred to as pseudohypertrophy rather than hypertrophy because it is due to fibroadipose
accumulation rather than muscle fiber enlargement, and is a sign of weakness rather than strength. Deep
tendon reflexes are initially normal. The diagnostic evaluation of these children is described in detail
below.
The weakness itself is steadily progressive as demonstrated by sequential neurologic examinations
(Boland et al, 1996; Brooke et al, 1989), but the functional abilities most visible to families may decline in a
more stepwise fashion (Brooke et al, 1983). There may be an apparent improvement in motor skills
between 3 and 6 years, while the functional decline typically accelerates after 8 years (Brooke et al,
1983). Without prednisone therapy, an affected child loses ambulation at a mean age of about 10 years,
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with a range typically from 7 to 13 years. With prednisone therapy, the mean age of loss of ambulation
may be delayed to 12 years (DeSilva et al, 1987). Further details on prednisone therapy may be found in
the therapy section.
Some affected individuals have essentially normal cognitive function, but a large number have mild static
impairments, measured to be on average one standard deviation below the mean, with especially
pronounced verbal impairments in many cases and emotional difficulties (Leibowitz, Dubowitz, 1981).
A major complication is scoliosis, which typically develops after the child begins to use a wheelchair
full-time. The scoliosis causes significant discomfort, social embarrassment, and functional difficulties. It
also can worsen respiratory function by decreasing the lung volume on one side, leading to diminished
vital capacity and atelectasis. The latter may increase the incidence of pneumonia.
Respiratory function is also compromised by diaphragm and intercostal muscle weakness. Pulmonary
complications form a leading cause of death, due to the combination of diminished vital capacity, weak
respiratory effort, and increased risk of pneumonias.
The other leading cause of death derives from cardiac complications, including cardiomyopathy and
arrhythmias (Brooke et al, 1989). The arrhythmias in particular are an unpredictable cause of death; fatal
rhythm disturbances typically occur later in the course but sometimes develop suddenly at an earlier age.
Without any treatment, the life expectancy rarely exceeds the adolescent years, and this was the
prognosis until the past several decades. A combination of improved diagnosis and therapies, as outlined
below, has lengthened the life expectancy significantly, such that many affected individuals now survive
past 30 years.
Becker Muscular Dystrophy
BMD is caused by the same gene as DMD; thus it is also X-linked recessive and almost always affects
males. The incidence has been estimated to be about 1 in 20,000 live male births. In contrast to DMD,
BMD patients typically have in-frame mutations, and thus some functional dystrophin protein is preserved
(Monaco et al, 1988). The phenotype is therefore milder, with onset usually in the second decade of life.
The range of severity is broad. Some patients lose the ability to walk independently during late
adolescence, while others remain ambulatory through most of adulthood. The cardiac complications are
the most serious ones; in fact, the cardiac manifestations may be the initial presentation of the condition in
some patients. Intelligence is usually normal.
Duchenne Muscular Dystrophy/Becker Muscular Dystrophy Intermediate Type
In some cases, boys with mutations in DMD will have a phenotype that is intermediate in age of onset and
severity between DMD and BMD. The prognosis also falls in the range between the two classic
diagnoses.
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Duchenne Muscular Dystrophy/Becker Muscular Dystrophy Carriers

Female carriers of DMD and BMD mutations express, on average, 50% of the normal level of dystrophin.
This is enough to prevent clinical weakness in most of these individuals. However, about 8% of carriers
have mild skeletal muscle involvement (Politano et al, 1996), most likely due to skewed X-inactivation
(Matthews, Karpati, 1996). The role of X-inactivation has been demonstrated in monozygotic twin female
carriers with divergent phenotypes (Burn et al, 1986; Lupski et al, 1991; Richards et al, 1990). The more
serious issue is potential cardiomyopathy, which often occurs in the absence of skeletal muscle
manifestations. The incidence of clinically significant cardiac abnormalities has been estimated to be from
0 to 15% in female carriers under the age of 16 (Nolan et al, 2003; Politano et al, 1996), and 44.5% in
adult carriers females (Politano et al, 1996). Adult female carriers should definitely have cardiac
evaluations including electrocardiograms and echocardiograms as soon as they are diagnosed. It is more
difficult to determine whether female carriers should have cardiac evaluations in childhood. Certainly, this
should become a consideration if the child experiences potential cardiac symptoms (easy fatigability,
chest pain, dyspnea on exertion, palpitations) or plans to participate in a competitive athletic activity.
X-Linked Dilated Cardiomyopathy
Some cardiomyopathies are inherited in an X-linked manner with little or no skeletal muscle involvement
associated with mutations in DMD. Some of these mutations are located in the promoter and 5 end of the
gene (Milasin et al, 1996; Muntoni et al, 1993), while other mutations interfere with cardiac-specific splice
sites (Ferlini et al, 1998). Notably, cardiomyopathy caused by Coxsackie virus B3 is associated with
cleavage of cardiac dystrophin by enteroviral protease 2A (Badorff et al, 1999).
Clinical Presentation and Natural History: Limb Girdle Muscular Dystrophies (LGMD)
LGMDs are a large class of muscular dystrophies that are caused by genes other than DMD (dystrophin).
The phenotype ranges widely, from those with early onset and severe disability resembling that of DMD,
to milder phenotypes that more closely resemble BMD. Were it not for the difference in inheritance
patterns and historic distinctions in classification, DMD, BMD, and LGMD could all be considered part of a
large family of childhood- and adult-onset progressive muscular dystrophies. The LGMDs are divided into
type 1 (autosomal dominant) and type 2 (autosomal recessive) categories. Type 1 appears to account for
less than 10% of cases to date, although this may be due in part to a lower rate of diagnosis in these
milder autosomal dominant conditions.
Cardiac complications are relatively frequent in types 1B, 1D, 2G, and 2I, but this list will likely expand in
the future as the various subtypes are studied in greater detail. Individuals with LGMD generally have
normal intelligence, although LGMD2K is associated with mental retardation. The genes that cause
certain LGMDs, such as 1B, 1C, 2B, 2I, and 2K, have also been associated with congenital muscular
dystrophy, other myopathies, and even primarily nonmuscular disorders. Specific mutations in CAV3 and
DYSF are associated with multiple phenotypes, raising the possibility that other genetic factors may
modify the phenotype.
LGMD1A: Myotilinopathy
The age of onset in LGMD1A is early adulthood. Initially, the weakness is proximal, but it becomes more
generalized as the disease progresses. These patients additionally have a distinctly dysarthric pattern of
speech. CK levels are markedly elevated.
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LGMD1A is caused by mutations in TTID, which encodes myotilin, a protein that forms part of the Z-disk in
the sarcomere (Hauser et al, 2000; Salmikangas et al, 1999). It appears to play a structural role, although
details remain unclear. Mutations in TTID cause Z-disk abnormalities, which may appear histologically as
rod-shaped structures resembling nemaline rods.
LGMD1B: Laminopathy
LGMD1B is characterized by proximal muscle weakness and a high rate of cardiac complications. The
latter makes sense in light of the genetic overlap with Emery-Dreifuss muscular dystrophy.
In addition to LGMD1B, mutations in LMNA can also cause Emery-Dreifuss muscular dystrophy, isolated
cardiomyopathy, lipodystrophy, and Hutchinson-Gilford progeria (De Sandre-Giovannoli et al, 2003;
Eriksson et al, 2003). It is unclear how a single gene can cause such diverse phenotypes in different
individuals. The two protein products, lamin A and lamin C, are produced by alternative splicing and
localize to the nuclear lamina.
LGMD1C: Caveolinopathy
Children with LGMD1C typically present at 5 years with proximal muscle weakness, calf hypertrophy, and
a Gowers sign. There have been occasional reports of exercise intolerance. CK levels are significantly
elevated.
Mutations in CAV3, the gene encoding caveolin 3, are responsible for cases of LGMD1C (Minetti et al,
1998). Other diseases caused by mutations in the same gene include rippling muscle disease (Betz et al,
2001; Kubisch et al, 2003), distal myopathy, and hyper-CKemia (Carbone et al, 2000). A single mutation
in CAV3 has been shown to cause rippling muscle disease with distal myopathy in some individuals, and
rippling muscle disease with LGMD in others.
LGMD1D
Onset of LGMD1D is typically in early adulthood, sometimes in late adolescence. Mild proximal weakness
may occur, but the most prominent manifestations are cardiac, including dilated cardiomyopathy and
cardiac conduction defects. Sudden death has occurred. The cardiac symptoms may precede the
weakness. CK levels are mildly elevated.
The responsible gene has not been identified. The locus has been linked to a 3-cM region of 6q23
(Messina et al, 1997). Two nearby laminins have been excluded as causative genes, but it is possible that
a previously unidentified laminin may be hiding in that region.
LGMD1E
Patients with LGMD1E have a proximal pattern of muscle weakness.
The gene has not been identified, but linkage analysis has narrowed the region to a 9-cM stretch on 7q
(Speer et al, 1999). The odds ratio for this region is not optimal; the genetic origins of this disorder remain
largely obscure.
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LGMD1F
LGMD1F is also known as vocal cord and pharyngeal weakness with autosomal dominant distal myopathy
(VCPDM), with onset typically in middle adulthood. The presentation may include voice change, finger
extensor weakness, peroneal weakness, shoulder girdle weakness, and dysphagia. CK levels may be
mildly elevated. Clinically it is a distal myopathy, and histologically there is little evidence for inflammation,
so it does not fit the typical picture of a muscular dystrophy.
The genetic locus has been narrowed to a 12-cM interval on 5q31 (Feit et al, 1998).
LGMD2A: Calpainopathy
To date, LGMD2A appears to be the most common single form of LGMD. It presents with progressive,
predominantly proximal weakness. Cardiac or facial involvement has not been documented thus far. The
severity varies widely, with many patients remaining ambulatory into the fifth decade. The phenotype does
not correlate consistently with calpain 3 expression levels in muscle tissue.
Mutations in CAPN3, which encodes the protein calpain 3, are responsible for LGMD2A (Richard et al,
1995). Following the initial report, a number of other mutations have been identified in various populations
(Dincer et al, 1997; Kawai et al, 1998; Penisson-Besnier et al, 1998; Richard et al, 1997; Topaloglu et al,
1997).
Deficiency of the calpain 3 protein has been documented on immunohistochemical analysis of muscle
tissue obtained from patients with LGMD2A (Anderson et al, 1998; Spencer et al, 1997). Calpain 3 is a
muscle-specific calcium-activated proteolytic enzyme, the first primarily nonstructural protein associated
with LGMD (Ono et al, 1998). Calpain 3 cleaves filamin 2, but the link between this function and the
phenotype remains unclear (Guyon et al, 2003a). The enzyme degrades quickly, making it difficult to
study. In human muscle biopsy tissue and mouse models, calpain 3 deficiency is associated with
myonuclear apoptosis and abnormal expression of NF-B and its inhibitor IB. As in other muscular
dystrophies, disruption of the sarcolemma in the mouse model was observed via injection of Evans blue
dye, which is membrane-impermeable. The relation of either phenomenon to the disease process is
unclear.
LGMD2B: Dysferlinopathy
LGMD2B presents with a proximal pattern of weakness, typically in childhood or early adulthood. CK
levels are markedly elevated. This disorder is milder than other autosomal recessive LGMDs; only about
10% of patients lose ambulation.
Mutations in DYSF, which encodes dysferlin, cause LGMD2B as well as Miyoshi myopathy and distal
myopathy with tibial onset (Bashir et al, 1998; Liu et al, 1998). The gene is large, consisting of 55 exons
and a 6243-bp open reading frame. The protein product is expressed mainly in skeletal and cardiac
muscles. Individual missense mutations have been observed to cause both LGMD2B and Miyoshi
myopathy in different individuals within the same family, while a single base pair deletion has been
observed to cause both Miyoshi myopathy and distal myopathy with tibial onset in different kindreds.
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LGMD2C-F: The Sarcoglycanopathies

The four sarcoglycanopathies present with progressive proximal muscle weakness, typically in the first
decade. LGMD2C, LGMD2D, LGMD2E, and LGMD2F correspond to -sarcoglycanopathy,
-sarcoglycanopathy, -sarcoglycanopathy, and -sarcoglycanopathy, respectively. SGCG, SGCA,
SGCB, and SGCD encode -, -, -, and -sarcoglycans and are the genes responsible for LMD2C,
LGMD2D, LGMD2E, and LGMD2F, respectively. The sarcoglycans associate with each other to form a
sarcolemmal protein complex (see below). Among them, LGMD2C (-sarcoglycanopathy) and LGMD2D
(-sarcoglycanopathy) tend to have a milder phenotype than LGMD2E (-sarcoglycanopathy) and
LGMD2F (-sarcoglycanopathy), although there is significant overlap between the range of phenotypes
seen in these disorders (OBrien, Kunkel, 2001). Symptomatic cardiomyopathy occurs in a minority of
patients, but subclinical cardiac disease is relatively common (Fadic et al, 1996; Gnecchi-Ruscone et al,
1999; Melacini et al, 1999; Prelle et al, 1998). As noted below, specific mutations have been noted to give
rise to a diversity of phenotypes, suggesting that the activity of modifying genes may have an impact on
the pathogenesis of these diseases.
LGMD2C (-sarcoglycanopathy) is caused by mutations in SGCG (McNally et al, 1996a; McNally et al,
1996b; Noguchi et al, 1995). A single mutation has been associated with a range of severity of the
disease (McNally et al, 1996b). This disease was initially identified in Tunisian kindreds, but reports of
SGCG mutations have been documented in other populations as well (Bonnemann et al, 2002; Buzzini,
Macmilan, 2001; Ginjaar et al, 2000; Lasa et al, 1998; Piccolo et al, 1996; Takano et al, 2000).
LGMD2D (-sarcoglycanopathy) is caused by mutations in SGCA (Piccolo et al, 1995; Roberds et al,
1993a; Roberds et al, 1994). It appears to be the most common among the sarcoglycanopathies, with a
prevalence of 5 to 10% among individuals with muscular dystrophy who do not have a dystrophinopathy
(Duggan et al, 1996; Duggan et al, 1997a). Most mutations appear to be in the extracellular domain
(Carrie et al, 1997). There is often a good correlation between the severity of the mutation, the degree of
protein deficiency, and the clinical phenotype (Eymard et al, 1997), but this is not uniform (Angelini et al,
1998; Higuchi et al, 1997).
LGMD2E (-sarcoglycanopathy) is caused by mutations in SGCB (Bonnemann et al, 1995; Lim et al,
1995). Genotype-phenotype correlations have been inconsistent in some cases (Bonnemann et al, 1998).
LGMD2F (-sarcoglycanopathy) is caused by mutations in SGCD (Duggan et al, 1997b; Nigro et al,
1996a; Nigro et al, 1996b).
LGMD2G
The onset of LGMD2G is typically in late childhood or adolescence with proximal weakness. In some
cases there may also be a distal pattern of weakness that resembles the phenotype of Miyoshi myopathy.
Many affected individuals lose the ability to ambulate independently by the third or fourth decade. Cardiac
complications occur frequently.
LGMD2G is caused by mutations in TCAP, which encodes telethonin (Moreira et al, 2000). Telethonin
localizes to the Z-disk of the sarcomere and is expressed in skeletal and cardiac muscles. Its specific
function is unknown, but it interacts with titin.
- 14 -
LGMD2H
Patients with LGMD2H have mild weakness that is slowly progressive.
The disease is caused by mutations in TRIM32, which encodes a protein with the same name that is an
E3 ubiquitin ligase expressed in skeletal and cardiac muscle (Frosk et al, 2002). It is possible that a
deficiency of the enzyme would cause the accumulation of its substrate, but histologic examination has
not revealed any unusual deposits in muscle fibers.
LGMD2I
There are two clinical forms of LGMD2I. In the severe form, children present in the first 2 years of life with
hypotonia, motor delays, and muscle hypertrophy (which may sometimes extend to macroglossia). The
course is similar to that of DMD, with frequent cardiac complications and loss of ambulation in early
adolescence. Some severe cases may resemble the phenotype of congenital muscular dystrophy 1C,
which is caused by mutations in the same gene.
The milder variant has been observed in a Tunisian family, with later onset and a slower progression.
Ambulation is preserved in nearly all cases. CK levels are markedly elevated in both forms.
Mutations in FKRP, which encodes fukutin-related protein, cause LGMD2I, as well as congenital muscular
dystrophy 1C (Brockington et al, 2001b). In contrast to the genotype-phenotype correlations with dysferlin,
different mutations in FKRP cause the two different phenotypes, suggesting that the mutations themselves
are primary determinants of the clinical manifestations. Patients with LGMD2I frequently have a
c.826CA, p.L276I mutation. In the more severe cases, secondary deficiencies of laminin-2 and
-dystroglycan may be observed on muscle tissue immunohistochemistry, western blots, or both.
LGMD2J
Patients with LGMD2J have proximal weakness with elevated CK levels.
LGMD2J is caused by mutations in TTN, which encodes titin (Haravuori et al, 2001). Titin is a large
sarcomeric protein that connects the M-line to the Z-disk. Immunohistochemistry of muscle tissue
obtained from affected individuals demonstrates a secondary deficiency of calpain 3.
LGMD2K
Individuals with LGMD2K tend to have relatively mild proximal muscle weakness with mild muscle
hypertrophy and marked elevations in serum CK levels. Onset in the small Turkish cohort identified so far
has been between 1 and 3 years, and patients appear to remain ambulatory at least until late adolescence
(Balci et al, 2005). Distinctive features include microcephaly and mental retardation, although no structural
abnormalities can be identified on brain imaging (Dincer et al, 2003). Muscle biopsies obtained from these
individuals demonstrated a reduction in -dystroglycan staining, suggesting the possibility of a primary
glycosylation defect. A mutation in POMT1 was identified (A200P), confirming that the primary
biochemical defect is in glycosylation (Balci et al, 2005).
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Clinical Presentation and Natural History: Congenital Muscular Dystrophies

The congenital muscular dystrophies (MDCs) are a growing category of degenerative muscle diseases
that are symptomatic from birth. These include some of the most severe and devastating muscular
dystrophies. There are three broad groups of MDCs: mild [laminin-2 (merosin)-positive and normal
cognition], moderate [laminin-2 (merosin)-negative and normal cognition], and severe
(laminin-2-negative with significant central nervous system abnormalities). Patients with the moderate
form have primary or secondary deficiencies in laminin-2, may have white matter abnormalities on
magnetic resonance imaging (MRI), and have normal or mildly delayed cognitive development. The
severe MDCs are accompanied by significant brain malformations and mental retardation, and typically
have a rapidly progressive course. Immunohistochemical staining typically shows a partial secondary
deficiency of laminin-2 in the severe forms.
Mild, Laminin-2 (Merosin)-Positive Congenital Muscular Dystrophies
The milder MDCs are characterized by normal staining of laminin-2 on immunohistochemical staining of
muscle tissue sections. Structural brain lesions are not typically found, and cognitive abilities are usually
normal. There are many cases of such MDCs that cannot be further characterized, but genetic mutations
have been linked to two MDC syndromes: Ullrich disease and rigid spine syndrome.
Infants with Ullrich disease have dramatic hypotonia, motor delays, and muscle atrophy. The diagnosis
may be suggested by the unusual combination of distal joint hyperextensibility and proximal joint
contractures. Cognition is normal. Some affected children walk for several years, but by the later stages
ambulation is always lost.
Mutations in COL6A1, COL6A2, and COL6A3 have been demonstrated to cause some cases of Ullrich
disease (Camacho Vanegas et al, 2001; Demir et al, 2002; Higuchi et al, 2001). These genes encode
collagen, type VI, 1, 2, and 3, respectively, and were initially associated with Bethlem myopathy
(Jobsis et al, 1996; Pan et al, 1998). Correspondingly, collagen VI has been found to be deficient on
immunohistochemistry of muscle tissue obtained from patients, whereas collagen IV expression is
upregulated, most likely as a secondary response. Collagen VI is expressed widely in connective tissues
and anchors collagen I/III fibrils to basement membranes.
Children with rigid spine syndrome generally have mild weakness. Most of them can eventually walk. CK
levels are normal or mildly elevated. However, they are at increased risk of developing respiratory
insufficiency requiring mechanical ventilation, perhaps due to selective weakness in the diaphragm.
Rigid spine syndrome is caused by mutations in SEPN1, which encodes selenoprotein N
(Moghadaszadeh et al, 2001). This protein incorporates selenium in the form of selenocysteine. The
function of selenoprotein N remains obscures, but selenium deficiency causes cardiomyopathy in humans
and muscular dystrophy in livestock.
Most children with laminin-2 (merosin)-positive congenital muscular dystrophy follow a mild course, aside
from the respiratory issues noted above. Further study may reveal other genes associated with this class
of diseases.
- 16 -
Moderate, Laminin-2 (Merosin)-Negative Congenital Muscular Dystrophy

The moderate forms of MDC are characterized by a more severe degree of motor involvement than the
mild forms with primary or secondary deficiencies in laminin-2. Neuroimaging typically reveals diffuse
white matter lesions in primary laminin-2 deficiency, but cognition is generally preserved.
MDC1A, or primary laminin-2 (merosin) deficiency, is the most common MDC, constituting about 40% of
all cases of MDC (Helbling-Leclerc et al, 1995; Tome et al, 1994). Infants present in the first 6 months of
life with muscle weakness, hypotonia, and contractures. Most affected individuals never walk
independently. Serum CK levels are mildly to moderately elevated. Diffuse white matter lesions are
evident on brain MRI, possibly due to merosin deficiency in the cerebral arteries (Villanova et al, 1996).
However, the gray matter and intelligence are generally preserved (Fig. 216-2). There have been some
reports of mental retardation. In some cases, seizures, cardiac complications, and neuronal migration
defects have been observed. The phenotype is sometimes milder (Sewry et al, 1997) and occasionally
presents as an inflammatory myopathy (Pegoraro et al, 1996). A milder variant resembling LGMD has
been described, although some of these patients may actually have LGMD2I.
Axial T2-weighted magnetic resonance imaging scan of the brain demonstrates marked hyperintense
signal in the cerebral white matter in a patient with merosin-deficient congenital muscular dystrophy.
Mutations in LAMA2 cause primary laminin-2 deficiency (Helbling-Leclerc et al, 1995; Hillaire et al, 1994;
Tome et al, 1994). In some cases, a missense mutation may cause a partial primary deficiency of
laminin-2 (Nissinen et al, 1996).
- 17 -
Some MDCs with secondary laminin-2 deficiency also cause a moderately severe phenotype, with
sparing of the central nervous system. These include MDC1C with fukutin-related protein deficiency
(Brockington et al, 2001a).
Severe Congenital Muscular Dystrophies
In order of generally increasing phenotypic severity, the three classic severe MDCs are Fukuyama
congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome
(WWS). They share a more severe course than the other MDCs, structural abnormalities in both the white
and gray matter of the brain, and significant mental retardation. The affected proteins all localize to the
Golgi apparatus and all appear to play a role in protein glycosylation, specifically of components of
-dystroglycan, which provides a biochemical link to laminin-2. Immunohistochemistry of muscle
sections obtained from affected patients demonstrates secondary deficiencies of both laminin-2 and
-dystroglycan. More recently, a mutation in LARGE, which encodes a glycosyltransferase with the same
name, has been linked to a form of MDC (MDC1D) with severe weakness, minimal ambulation, and
severe mental retardation (Longman et al, 2003).
FCMD is most common in Japan, with an incidence of about 1 in 10,000 live births (Fukuyama et al, 1981;
Kamoshita et al, 1976; Kobayashi et al, 1998b). Infants with FCMD have severe weakness and hypotonia.
They rarely walk independently. Brain lesions may include cortical and cerebellar dysgenesis (especially
polymicrogyria), cerebellar cysts, hydrocephalus, and white matter abnormalities, resulting in mental
retardation and epilepsy in many cases (Aida et al, 1996; Aida et al, 1994). There is a broad range of
clinical severity (Kondo-Iida et al, 1997; Saito et al, 2000; Yoshioka, Kuroki, 1994; Yoshioka et al, 1999).
Most affected individuals eventually sit but do not walk, and life expectancy may extend to early
adulthood. However, in the most severe cases, motor development is very poor with survival only for a
few years, and in rare cases at the milder end of the spectrum, patients may be able to walk.
Mutations in FCMD, which encode fukutin, cause FCMD. The most common mutation is a 3-kb
retrotransposal insertion in the 3 untranslated region of the gene (Kobayashi et al, 1998a). Point
mutations have also been reported. In either case, the protein is completely absent in muscle tissue.
Fukutin plays a role in glycosylation of -dystroglycan.
Infants with MEB have severe weakness with hypotonia; most do not become ambulatory. The ocular
problems include myopia, glaucoma, optic disc pallor, and retinal hypoplasia. Structural brain lesions
include lissencephaly, a flattened brainstem, cerebellar hypoplasia, and white matter changes. Mental
retardation is uniformly present, and epilepsy commonly occurs. With supportive care, life expectancy can
be into early adulthood.
Mutations in POMGnT1 (O-mannose -1,2-N-acetylglucosaminyltransferase), which encodes a protein
with the same name, cause MEB (Yoshida et al, 2001). The protein product is a glycosyltransferase found
in the Golgi apparatus that catalyzes the transfer of N-acetylglucosamine from UDP-GlcNAc to
O-mannosyl glycoproteins, which is the second step in the biosynthesis of O-mannosylglycan, a
component of -dystroglycan.
WWS is perhaps the most severe muscular dystrophy. Patients rarely survive infancy, and a number
probably die in utero, since mothers of affected infants often report a history of miscarriages. The clinical
presentation includes severe weakness and hypotonia. Brain malformations may include cobblestone
lissencephaly, agenesis of the corpus callosum, cerebellar hypoplasia, hydrocephalus, and extensive
- 18 -
white matter abnormalities. Other problems may include buphthalmos, glaucoma, other eye abnormalities,
and testicular defects. Serum CK levels are moderately elevated.
To date, the most common causative gene appears to be POMT1 (O-mannosyltransferase)
(Beltran-Valero de Bernabe et al, 2002). Mutations in this gene have been identified in six different
families. Isolated cases of WWS have been associated with mutations in FCMD and FKRP.
Clinical Presentation and Natural History: Distal Myopathies with Dystrophic Features
The distal myopathies have in recent years expanded to become a sizable class of disorders. Two of
them, Miyoshi myopathy and tibial muscular dystrophy (Udd myopathy), are allelic with limb girdle
muscular dystrophies 2B and 2J, respectively, and have dystrophic findings on muscle biopsy. These two
will be described briefly. The other classic distal myopathies, Welander myopathy, Nonaka myopathy, and
Laing myopathy, are beyond the scope of this discussion.
Miyoshi Myopathy
Miyoshi myopathy was recognized and described separately in Japan (Miyoshi et al, 1977) and the United
States (Markesbery et al, 1977). Inheritance is autosomal recessive, and onset is typically in late
adolescence or early adulthood, with early involvement of the gastrocnemius muscle. A cardinal sign is
difficulty or inability to stand on tiptoes. Other skeletal muscles may also be affected, but to a lesser
extent. CK elevation is typical, as are myopathic findings on electromyography. Muscle histology
demonstrates a dystrophic pattern (Miyoshi et al, 1986), with advanced fibrosis in gastrocnemius,
intermediate findings in biceps femoris, and only scattered necrotic fibers in vastus lateralis, suggesting
that biceps femoris is the optimal muscle to sample for analysis (Barohn et al, 1991). Miyoshi myopathy is
caused by homozygous or compound heterozygous mutations in DYSF, the same gene that causes
LGMD2B (Liu et al, 1998).
Tibial Muscular Dystrophy
Tibial muscular dystrophy (Udd myopathy) is inherited in an autosomal dominant manner, with onset later
than 35 years and selective involvement of the tibialis anterior muscle. Extensor digitorum brevis, which is
also innervated by the peroneal nerve, is preserved. Serum CK levels are mildly elevated in the majority of
patients, electromyography of affected muscles demonstrates myopathic features, and dystrophic findings
are present on muscle biopsy, sometimes accompanied by vacuolar changes (Udd et al, 1993). The
selection of the muscle to be biopsied is important, as asymptomatic muscles may show few histologic
signs of disease (Udd et al, 1993). Tibial muscular dystrophy is caused by mutations in TTN, the same
gene implicated in LGMD2J (Hackman et al, 2002).
In rare cases, a homozygous mutation in DYSF may cause a similar phenotype of distal myopathy with
anterior tibial onset (DMAT) (OMIM 606768), with an autosomal recessive inheritance (Liu et al, 1998).
Clinical Presentation and Natural History: Syndromic and Miscellaneous Muscular Dystrophies
All of the muscular dystrophies in this section have fairly unique phenotypes and cannot easily be included
in any of the above categories.
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Bethlem Myopathy
The initial description of Bethlem myopathy outlined a relatively benign autosomal dominant disorder
characterized by onset around age 5 years, with contractures at the elbows and interphalangeal joints
(Bethlem, Wijngaarden, 1976). This classic presentation has generally been confirmed by other
observers, with a broader range of severity than was first recognized. On the milder end of the spectrum,
symptoms may be very subtle in relatives of affected individuals, and onset may be delayed until middle
adulthood (Merlini et al, 1994). Longer follow-up and evaluation of larger cohorts have demonstrated that
affected children may have congenital hypotonia and contractures, and that after the age of 50 years, the
majority of patients require the use of a wheelchair (Jobsis et al, 1999).
Mutations in COL6A1, COL6A2, and COL6A3 cause Bethlem myopathy as well as Ullrich congenital
muscular dystrophy (Jobsis et al, 1996; Pan et al, 1998).
Emery-Dreifuss Muscular Dystrophy
The symptoms of Emery-Dreifuss muscular dystrophy (EDMD) begin in the first decade of life, and may
including toe-walking and limitation of movement at the elbows, neck, and spine. The selective pattern of
contractures in EDMD is striking and unique, involving the posterior neck, elbows, and heel cords. In early
childhood, only the heel cord contractures may be present. Contractures are typically more prominent
than muscle weakness. Muscle weakness and atrophy in a humeroperoneal distribution typically begin in
the second decade. Cardiac conduction defects leading to heart block are common in affected individuals
and some carriers and may be life-threatening, especially during anesthesia (Hopkins et al, 1981; Jensen,
1996). This complication may be treated by the insertion of a cardiac pacemaker. Intelligence is usually
normal. A clinical variant resembling LGMD has been identified (Muntoni et al, 1998).
Two genes are known to cause EDMD: EMD and LMNA. EMD is a 2-kb, 6-exon gene located at Xq28
(Bione et al, 1994). After the gene was identified, further mutations were found (Bione et al, 1995;
Ichikawa et al, 1997; Klauck et al, 1995; Nigro et al, 1995; Wulff et al, 1997a; Wulff et al, 1997b; Yamada,
Kobayashi, 1996). Large inverted repeats flank the EMD gene, making it susceptible to large-scale partial
or whole-gene deletions (Small et al, 1997; Small, Warren, 1998). LMNA is the second causative gene
and is located at 1q21.2-q21.3 (Bonne et al, 1999). The disease is inherited in an X-linked recessive
fashion when associated with EMD and in an autosomal dominant or recessive fashion when LMNA is
involved (Raffaele Di Barletta et al, 2000). Mutations in LMNA can cause several other diseases, including
LGMD1B, cardiomyopathy, lipodystrophy, and Hutchinson-Gilford progeria.
Emerin, the protein product of EMD, is expressed ubiquitously but is predominantly found in skeletal
muscle, heart, colon, testis, ovary, and pancreas. Emerin localizes to the inner nuclear membrane via the
hydrophobic C-terminal domain (Manilal et al, 1996; Nagano et al, 1996). Emerin and lamin A interact at
the nuclear lamina (Clements et al, 2000; Manilal et al, 1998).
Facioscapulohumeral Muscular Dystrophy
The onset of facioscapulohumeral muscular dystrophy (FSHD) is typically in the second decade. Males
are more severely affected than females (Zatz et al, 1998). Affected individuals have a distinct pattern of
muscle wasting and weakness. The muscles most characteristically affected are in the face, shoulder
girdle, and upper arm. Pelvic girdle, forearm, and peroneal muscles may also be affected later.
Sensorineural hearing loss and retinal vasculopathy (telangiectasias) may occur, requiring periodic
hearing evaluations and ophthalmologic monitoring (Funakoshi et al, 1998). Intelligence is often normal
but a subset of patients develop mental retardation (Funakoshi et al, 1998). The majority of patients
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remain ambulatory. Cardiac involvement is variable (Laforet et al, 1998). Phenotypic variants that have
been linked to the same genetic locus include scapuloperoneal and scapulohumeral dystrophies.
The exact genetic etiology of FSHD has been a longstanding mystery, but new clues may be emerging.
The disease has been mapped to a region on 4q35 (Upadhyaya et al, 1992; Wijmenga et al, 1990;
Wijmenga et al, 1991), and patients with FSHD have deletions in a D4Z4 tandem repeat sequence (Hewitt
et al, 1994; van Deutekom et al, 1993), making it possible to perform genetic testing (Bakker et al, 1996).
Each D4Z4 sequence is 3.3 kb in length and contains two homeobox domains. Affected individuals have
fewer than 11 of these repeats. The severity of the deletion tends to correlate with the severity of the
disease (Lunt et al, 1995). Many cases are familial, while sporadic cases may arise from germline
mosaicism (Roques et al, 1998). The deletion is stably inherited within families. Other factors appear to be
involved in the pathogenesis, as monozygotic twins with identical D4Z4 deletions have been reported to
have divergent phenotypes (Tupler et al, 1998). Also complicating matters is the presence of a
homologous region on 10q that is not pathogenic (Cacurri et al, 1998); a method was developed to
distinguish between the two (Deidda et al, 1996; Upadhyaya et al, 1997).
The mystery has surrounded the lack of a known coding region within the D4Z4 sequence. Neither an
RNA transcript nor a protein product has been identified. The most likely mechanism appears to be
position effect variegation. This was suggested by the upregulation of a number of genes upstream of the
D4Z4 region. Ordinarily, a protein complex consisting of YY1, HMGB2, and nucleolin binds to the D4Z4
region and mediates transcriptional repression of the upstream genes, including ANT1, FRG1, and FRG2.
A deletion in the D4Z4 region could conceivably disrupt this balance, leading to overexpression of the
upstream genes (Gabellini et al, 2002). Overexpression of ANT1, FRG1, and FRG2 in a mouse model
resulted in a dystrophic phenotype in the mice who overexpressed FRG1 but not the other two genes; this
was demonstrated via observation of kyphosis, muscle atrophy, histology, and alternative splicing patterns
of Tnnt3 and Mtmr1 (Gabellini et al, 2006). The alternative splicing of TNNT3 and MTMR1 was also
shown in muscle cell cultures derived from human FSHD patients (Gabellini et al, 2006). These results
suggest that upregulation of FRG1 is the mechanism by which FSHD develops, but further studies may be
required to confirm this.
Oculopharyngeal muscular dystrophy
Oculopharyngeal muscular dystrophy (OPMD) was originally described as an inherited syndrome
characterized by ptosis and dysphagia (Taylor, 1915). In many regions it is rare, with a prevalence of 1 in
200,000 for the autosomal dominant type in France (Brunet et al, 1990). However, certain populations
have a higher prevalence, including French-Canadians (Brais et al, 1997) and Bukhara Jews living in
Israel (Blumen et al, 1997). The presentation of the dominant form of OPMD typically occurs between
ages 50 and 70 with dysphagia, ptosis, and proximal muscle weakness (Victor et al, 1962). Other signs
may include facial weakness, limitation of upgaze, dysphonia, and tongue atrophy and weakness
(Bouchard et al, 1997). The recessive phenotype is similar, although the severity may be milder (Fried et
al, 1975). Pathologically, nuclear filamentous inclusions are found in muscle fibers of affected individuals
with both dominant and recessive forms of the disease and are regarded to be specific histologic markers
for the disease (Blumen et al, 1996; Brais et al, 1998; Coquet et al, 1990; Tome, Fardeau, 1980).
OPMD is the only muscular dystrophy caused by a triplet repeat expansion, unless myotonic dystrophy is
regarded primarily as a muscular dystrophy rather than a myotonic disorder. In normal individuals,
PABP2, which encodes poly(A) binding protein 2, contains a (GCG) 6 repeat in exon 1. Individuals
affected with OPMD have a (GCG) 8-13 expansion in exon 1 (Brais et al, 1998). In contrast to other triplet
repeat diseases, the expansion has a low copy number and is stably inherited. The disease is typically
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inherited in an autosomal dominant fashion, but a borderline (GCG) 7 expansion on the other allele may
worsen the phenotype typically expected for the size of the longer expansion. In rare cases, a
homozygous (GCG) 7 expansion can cause a mild form of OPMD that is inherited in an autosomal
recessive manner.
Genetics and Biochemistry
Dystrophin
The complete sequence of the DMD gene was published soon after the initial exons were cloned (Koenig
et al, 1987). It is the largest gene identified to date with respect to the total number of base pairs (2.3
million) ( http://genome.ucsc.edu), although TTN (see below) has a greater number of exons and a larger
protein product (titin). The DMD gene has 79 exons (Coffey et al, 1992; Roberts et al, 1993) and is
transcribed at about 40 nucleotides per second, with a total transcription time of 16 hours (Tennyson et al,
1995). This was the first description of cotranscriptional splicing in a mammalian cell (Tennyson et al,
1995). Deletions form approximately two-thirds of mutations found in affected patients, and they tend to
cluster in exons 2 to 20 and 44 to 53 (Gillard et al, 1989; Koenig et al, 1989). The intronic sequences
between these exons tend to be unusually long, nearly 200 kb, which accounts for their vulnerability to
deletions.
In skeletal muscle, DMD encodes a 427-kDa protein called dystrophin that represents 0.002% of total
muscle protein (Hoffman et al, 1987) and 5% of membrane cytoskeleton (Ohlendieck, Campbell, 1991). It
is a monomeric protein (Chan, Kunkel, 1997; Rybakova, Ervasti, 1997) that was first localized to the
sarcolemmal region (Arahata et al, 1988; Bonilla et al, 1988; Zubrzycka-Gaarn et al, 1988), and then more
specifically to the subsarcolemma (Watkins et al, 1988). The skeletal muscle isoform is composed of 3685
amino acids and has four major domains: amino terminus, rod domain, cysteine-rich domain, and
carboxy-terminus (Koenig et al, 1988). The amino terminus binds to F-actin and resembles the
corresponding regions of -actinin and -spectrin (Rybakova et al, 1996). The rod-like domain contains 24
spectrin-like repeats and 4 hinge segments, and is 15 to 20 nm from the cytoplasmic face of the
sarcolemma (Cullen et al, 1991; Koenig, Kunkel, 1990). Hinge 4 and the cysteine-rich domain of
dystrophin bind to the 15 C-terminal amino acids of -dystroglycan, thus connecting dystrophin to the
extracellular matrix (Jung et al, 1995; Koenig et al, 1988). Both the amino terminus and rod domains bind
to F-actin (Rybakova et al, 1996); in mice, a deletion of just the amino terminus results in a mild
phenotype (Corrado et al, 1994; Corrado et al, 1996), while deletions in both domains cause a more
severe phenotype (Cox et al, 1994), suggesting that the F-actin binding property is an important function
of dystrophin.
There is also a high concentration of dystrophin at the myotendinous junction (Byers et al, 1991) and the
postsynaptic portion of the neuromuscular junction (Huard et al, 1992b). It appears that dystrophin has a
structural function and protects muscle from damage during contractions (Petrof et al, 1993; Weller et al,
1990), although it may also play a more dynamic role such as regulation of the repair and perfusion of
muscle through its association with syntrophin and in turn nitric oxide synthase (see below) (Brenman et
al, 1996; Rando, 2001). Dystrophin is also present in the subplasmalemmal region of cardiac and smooth
muscle; its expression in the latter is relatively patchy (Byers et al, 1991; Hoffman et al, 1988b).
There are three major sources of variation in dystrophin expression that lead to the various known
isoforms: alternative promoters, variable lengths of transcripts, and splice variations in the carboxy
terminus. Full-length transcripts that differ by only a few base pairs are produced in muscle, cardiac
Purkinje fibers, and brain with alternative promoters (Bies et al, 1992; Boyce et al, 1991; Chamberlain et
- 22 -
al, 1988b; Nudel et al, 1988). The brain also expresses a shorter, Dp140 isoform postsynaptically (Lidov
et al, 1993; Lidov et al, 1990; Lidov et al, 1995). The Dp116 isoform is present in Schwann cells (Byers et
al, 1993), Dp260 in retina (DSouza et al, 1995), and Dp71 in other nonmuscle tissues, including a
different location in the retina (Howard et al, 1998; Rapaport et al, 1992; Yaffe et al, 1992). Further
diversity in dystrophin expression is created by splice variations at the carboxy terminus (Feener et al,
1989; Lidov, 1996).
Deficiency of dystrophin appears to cause mechanical weakness in the sarcolemma, followed by
disruptions of the sarcolemma during muscle contraction (Menke, Jockusch, 1991). This leads to an influx
of calcium (Carpenter, Karpati, 1989) into the muscle fiber, followed by mitochondrial calcium overload
that leads to impairment of oxidative phosphorylation and muscle fiber necrosis (Mezon et al, 1974;
Wrogemann et al, 1970; Wrogemann et al, 1973).
Dystrophin-Associated Protein Complex
Several years after the cloning of dystrophin, it became apparent that it was associated with a number of
other proteins, including a sarcolemmal glycoprotein (Campbell, Kahl, 1989; Ervasti et al, 1990; Yoshida,
Ozawa, 1990). This large cluster of proteins forms the DAPC (Fig. 216-3) (Ervasti, Campbell, 1991). The
complex has traditionally been divided into three clusters (Dalkilic, Kunkel, 2003; Yoshida, Ozawa, 1990),
but the recent discovery that biglycan links the sarcoglycan and dystroglycan clusters suggests that the
complex may alternatively be divided into two main categories: sarcolemmal and subsarcolemmal.
The current knowledge of the cellular localization of the dystrophin-associated protein complex, as well as
many of the other proteins involved directly or indirectly in the pathogenesis of the muscular dystrophies.
The proteins located at the sarcolemma include -dystroglycan and -dystroglycan, biglycan,
-sarcoglycan (Piccolo et al, 1995; Roberds et al, 1993a), -sarcoglycan (Bonnemann et al, 1995;
Bonnemann et al, 1996; Lim et al, 1995), -sarcoglycan (McNally et al, 1996a; McNally et al, 1996b;
- 23 -
Noguchi et al, 1995), -sarcoglycan (Jung et al, 1996; Nigro et al, 1996a; Nigro et al, 1996b),
e-sarcoglycan (Ettinger et al, 1997; McNally et al, 1998), and sarcospan (Crosbie et al, 1997; Crosbie et al,
1999). Dystrophin binds to -dystroglycan (43 kDa), which binds to -dystroglycan (156 kDa), which in
turn binds to laminin-2, part of the extracellular matrix (Ibraghimov-Beskrovnaya et al, 1992). A single
gene, DAG1, encodes both - and -dystroglycan, which contribute to basement membrane assembly
(Henry, Campbell, 1998). Based on embryonic lethality in mouse models and the lack of an identified
human disease resulting from dystroglycan deficiency, it is most likely that primary dystroglycan deficiency
is an embryonic lethal mutation in humans (Williamson et al, 1997). -dystroglycans association with
Grb2 (Oak et al, 2001) suggests that it plays a signaling as well as structural role at the sarcolemma
(Yang et al, 1995). The sarcoglycans are very similar to one another. Each one has a single
transmembrane domain, small intracellular domain, and large extracellular domain. They range from 35 to
50 kDa, and all are glycosylated.
Biglycan is a proteoglycan that associates with -dystroglycan, - and -sarcoglycan, and collagen VI,
linking the dystroglycan cluster to the sarcoglycan cluster in the sarcolemma (Bowe et al, 2000; Wiberg et
al, 2001; Wiberg et al, 2002). The link to collagen VI also provides a second link to the extracellular matrix
for -dystroglycan. -, -, -, and -sarcoglycan are linked with LGMD2C-F (see above). However,
deficiencies in -sarcoglycan cause myoclonus-dystonia syndrome rather than a muscular dystrophy
(Asmus et al, 2002; Zimprich et al, 2001). Maternal imprinting plays a role in the pathogenesis of this
disorder. -sarcoglycan replaces -sarcoglycan in smooth muscle (Straub et al, 1999). Sarcospan
interacts with the sarcoglycan complex (Crosbie et al, 1999). A small portion of the filamin C (gene symbol
FLNC, gene previously known as FLN2 and protein previously known as filamin) in the muscle fiber
interacts with - and -sarcoglycan, and its localization is altered in DMD and LGMD (Thompson et al,
2000). Calpain 3 associates with and cleaves filamin C (Guyon et al, 2003a). Most of the filamin C
localizes to the sarcomeric Z disk (see below).
The subsarcolemmal component of the DAPC includes dystrophin itself, 1-, 1-, and 2-syntrophin
(Adams et al, 1993; Ahn et al, 1996; Ahn et al, 1994), - and -dystrobrevin (Peters et al, 1997; Puca et
al, 1998; Sadoulet-Puccio et al, 1996), and nitric oxide synthase (Crawford et al, 2000; Grady et al, 1999).
The carboxy terminus coiled coil domains of dystrophin and the dystrobrevins associate (Sadoulet-Puccio
et al, 1997). Syntrophins bind to both dystrophin and the dystrobrevins (Ahn, Kunkel, 1995; Suzuki et al,
1995). Nitric oxide synthase binds to the syntrophins (Hillier et al, 1999), is absent in DMD and BMD
(Brenman et al, 1995; Chao et al, 1996), and is displaced in the dystrophic mouse model of -dystrobrevin
deficiency, impairing nitric oxide-mediated signaling (Grady et al, 1999). The -syntrophin null mouse
does not have a dystrophic phenotype, but the muscle tissue lacks nitric oxide synthase and has other
mild histologic abnormalities (Adams et al, 2000). These findings suggest that the DAPC potentially plays
a role in signaling, muscle fiber repair, or both in addition to its structural function (Brenman et al, 1996;
Rando, 2001). Curiously, -dystrobrevin null mice do not have perceptible phenotypic abnormalities
(Grady et al, 2006). nNOS and eNOS null mice have signaling abnormalities in skeletal muscle (Lau et al,
2000). F-actin binds to the amino terminus of dystrophin (Levine et al, 1992), and laminin-2 binds to
-dystroglycan, but these are generally not considered part of the DAPC proper.
When other proteins in the DAPC are deficient, as is found in other muscular dystrophies, the effect on
dystrophin expression is variable. In some cases, dystrophin expression is normal (Ben Jelloun-Dellagi et
al, 1990).
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Other Sarcolemmal Proteins

Utrophin is a close analogue of dystrophin (Buckle et al, 1990; Ishiura et al, 1990; Khurana et al, 1990;
Love et al, 1989; Nicholson et al, 1989) that is expressed throughout the sarcolemma during development
but localizes only to the neuromuscular and myotendinous junctions in mature muscle (Karpati et al,
1993b; Khurana et al, 1991; Ohlendieck et al, 1991; Voit et al, 1991). In mice, utrophin deficiency alone
produces only mild abnormalities (Deconinck AE et al, 1997a; Grady et al, 1997a), while utrophin
deficiency in mdx mice worsens the mdx phenotype (Deconinck AE et al, 1997b; Grady et al, 1997b), and
utrophin overexpression improves the mdx phenotype (Deconinck N et al, 1997; Rafael et al, 1998). This
suggests that utrophin may be able to compensate to some extent for dystrophin deficiency.
Caveolae are 50- to 100-nm invaginations of the plasma membrane of most cells, including the
sarcolemma of muscle fibers. Sarcolemmal caveolae contain dysferlin and caveolin 3, which interact with
each other (Matsuda et al, 2001; Tang et al, 1996). Caveolins participate in membrane trafficking, sorting,
transport, and signal transduction. Caveolin 3 is specific to muscle, interacts with -dystroglycan, and
colocalizes with dystrophin, linking it to the DAPC (Song et al, 1996; Sotgia et al, 2000). It forms a hairpin
loop within the sarcolemma, enabling both the amino and carboxy terminals to come in contact with the
cytoplasm. Abnormal expression of caveolin 3 in mouse models leads to a deficiency of caveolae and
abnormalities in the T tubule system, while in humans it causes LGMD. Dystrophin deficiency leads to
overexpression of caveolin 3 (Repetto et al, 1999), while overexpression of caveolin 3 leads to dystrophin
deficiency (Galbiati et al, 2000).
Dysferlin is homologous to the Caenorhabditis elegans protein fer-1, which plays a role in vesicle fusion
(Achanzar, Ward, 1997). In human tissue, dysferlin has been demonstrated to participate in the
calcium-dependent process of membrane resealing after sarcolemmal injury, suggesting that this repair
mechanism is defective in at least some forms of muscular dystrophy (Bansal, 2003; Lennon et al, 2003).
Dysferlin deficiency can cause several different muscle disorders (see LGMD2B and Miyoshi myopathy
above), suggesting that modifying genes influence the phenotype (Liu et al, 1998; Weiler et al, 1999).
Integrin 7 and integrin 1 form a small laminin receptor complex in the sarcolemma with no apparent
direct links to the DAPC. Integrin 7 deficiency is associated with a dystrophic phenotype in mice (Mayer
et al, 1997), but in humans it produces a form of congenital myopathy (Hayashi et al, 1998). Among other
functions, the complex appears to assist in the adhesion of muscle fibers to each other to generate
contractile force (Burkin, Kaufman, 1999).
Extracellular Matrix
There are two major types of structural proteins in the extracellular matrix (ECM) that have been linked to
muscular dystrophy: the laminins and collagens. LAMA2 is a 64-exon gene that encodes laminin-2,
which is deficient in MDC1A, merosin-negative congenital muscular dystrophy (Tome et al, 1994). Merosin
is the term for a laminin that contains an 2 heavy chain.
Sarcomere
Actin and myosin were the first major components of the sarcomere that were identified; they are major
components of the contractile apparatus. The structure of the sarcomere has become much more detailed
in recent years, and its complexity is astounding. Several sarcomeric proteins, including myotilin,
telethonin, and titin, have been implicated in various LGMDs. In the Z disk, titin interacts with telethonin
(Mues et al, 1998) and myotilin interacts with filamin C, -actinin, and F-actin (Salmikangas et al, 2003;
van der Ven et al, 2000). Deficiencies in titin cause secondary deficiencies in calpain 3 (Haravuori et al,
- 25 -
2001).
Golgi Complex
Several proteins that localize primarily in the Golgi complex play a role in glycosylation of the
dystroglycans that link the DAPC to the ECM. These proteins include fukutin, fukutin-related protein,
POMGnT1, POMT1, and most recently LARGE (Brockington et al, 2005; Michele et al, 2002). Deficiencies
in these proteins usually cause the severe forms of congenital muscular dystrophy, and occasionally
milder LGMDs. The connection to the dystroglycans and indirectly to laminin-2 provides a link between
some of the proteins that are responsible for the MDCs.
The POMT1 protein, like fukutin and POMGnT1, plays a role in glycosylation, as demonstrated by the
absence of -dystroglycan glycosylation in muscle sections obtained from affected individuals. The overall
amount of -dystroglycan is also reduced in muscle tissue from these patients. POMT1 is ubiquitous, but
peak levels of expression can be found in skeletal and cardiac muscle, fetal brain, and adult testis,
correlating with the phenotypic involvement.
The first glycosyltransferase associated with a muscular dystrophy was in the myd mouse, subsequently
renamed LARGE myd (Grewal et al, 2001; Longman et al, 2003). This mouse was originally thought to be a
model for FSHD but was subsequently found to have a mutation in Large, with 98% homology to human
Large (Grewal et al, 2001).
Sarcoplasmic Reticulum
The major protein in the sarcoplasmic reticulum associated with a muscular dystrophy is selenoprotein N,
1. A deficiency in this protein can cause rigid spine syndrome or multiminicore myopathy. The latter is,
strictly speaking, a variant of a congenital myopathy rather than a muscular dystrophy.
Nucleus
Several nuclear proteins, including lamin A/C, emerin, and poly(A) binding protein 2, are associated with
unique forms of muscular dystrophy. Lamin A/C is particularly intriguing as deficiencies may be
responsible for one of a broad range of diseases: Emery-Dreifuss muscular dystrophy, LGMD,
Charcot-Marie-Tooth disease type 2, Hutchinson-Gilford progeria (De Sandre-Giovannoli et al, 2003;
Eriksson et al, 2003), familial partial lipodystrophy, dilated cardiomyopathy, and mandibuloacral dysplasia.
Lamin A and lamin C are structural proteins of the nuclear envelope encoded by the same gene, LMNA,
via alternative splicing. Lamin A is 664 amino acids long, while lamin C is 572 amino acids in length.
Poly(A) binding protein 2 localizes to the nucleus (Krause et al, 1994) and is involved in the second phase
of mRNA polyadenylation (Wahle, 1991). A pathologic expansion of the GCG triplet repeat sequence
results in a longer polyalanine region that forms -sheet structures resistant to protease degradation
(Forood et al, 1995). Nuclear function may then be irreparably impaired.
FRG1 may be the gene that causes FSHD; its expression is increased indirectly via deletion of the D4Z4
region on 4q35 and plays a role in mRNA splicing (Gabellini et al, 2006).
- 26 -
Enzymes
There are two enzymes linked to the LGMDs: calpain 3 and TRIM32. Calpain 3 is a calcium-activated
neutral protease while TRIM32 appears to be a ligase (Frosk et al, 2002; Richard et al, 1995).
Animal Models
The DAPC has been identified in a number of different organisms, among which several animal models of
muscular dystrophy have been identified. The animal models used most extensively are in the mouse,
dog, and zebrafish.
Mice and Other Rodents
The most extensively studied mouse model of DMD is the mdx mouse, a naturally occurring animal model
that has a nonsense mutation in exon 23 of mouse dystrophin (Bulfield et al, 1984; Ryder-Cook et al,
1988; Sicinski et al, 1989). Curiously, the phenotype of the mdx mouse is much milder than DMD in
humans (Durbeej, Campbell, 2002; Sicinski et al, 1989). Between 2 and 6 weeks of age, mdx hindlimb
muscles exhibit intense necrosis and regeneration, after which the muscles undergo stabilization, and
then hypertrophy and dystrophic degeneration as the mice age (Hoffman, Gorospe, 1991; McArdle et al,
1994). The one mdx mouse muscle that undergoes extensive degeneration similar to that found in human
DMD muscle is diaphragm (Cullen, Jaros, 1988; Stedman et al, 1991). A combined dystrophin-utrophin
mouse has been developed, and this model more closely replicates the phenotype of DMD (see
discussion of utrophin in Other Sarcolemmal Proteins, above).
Other mouse models of dystrophin deficiency have been developed. One that is becoming more widely
used in studies of muscular dystrophy is the mdx 5cv mouse, which has a mutation in exon 10 of
dystrophin generated by ethylnitrosurea mutagenesis (Chapman et al, 1989). This mutation creates a
novel splice site that induces aberrant splicing and an absence of dystrophin. The mdx 5cv phenotype is
more severe than the mdx one, but is still less severe than DMD. Mdx 5cv mouse muscles have 10 times
fewer revertant (dystrophin-positive) fibers than do those of mdx mice.
The differences in phenotypic severity among DMD and its various mouse models suggest that secondary
factors modulate the pathogenesis of the disease. This is also supported by the differential response of
specific muscle groups in mice and humans to dystrophin deficiency (Deconinck et al, 1998; Kaminski et
al, 1992; Karpati, Carpenter, 1986; Khurana et al, 1995; Matsumura et al, 1992; Moens et al, 1993).
Molecular differences between a limited number of muscle groups have been examined in mdx mice using
gene expression technology (Porter et al, 2002; Porter et al, 2003; Rouger et al, 2002; Tkatchenko et al,
2000; Tseng et al, 2002). One study in particular focused on a comparison of diaphragm and hindlimb
muscles (Porter et al, 2004), while another performed a broad survey of six different muscles: diaphragm,
soleus, extensor digitorum longus, quadriceps, gastrocnemius, and tibialis anterior (Haslett et al, 2005).
Among these six mouse muscles, soleus bears the closest molecular similarity to several human skeletal
muscles (Kho et al, 2006).
The other classic mouse model of muscular dystrophy is the naturally occurring dy/dy mouse, which has
been studied for decades (Meier, Southard, 1970). It has a more severe phenotype than the mdx mouse.
However, the genetic defect was mapped to the same locus as LAMA (laminin-2) rather than DMD, and
the mice were found to be deficient in the expression of laminin-2 (merosin) (Sunada et al, 1994; Xu et
al, 1994a). The genetic defect is a splice-site alteration that removes 57 amino acids from domain VI of
the protein, which would most likely disrupt self-aggregation of laminin heterotrimers (Sunada et al, 1995;
Xu et al, 1994b).
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More recently, several mouse models of the sarcoglycanopathies have been developed. Cardiomyopathy
is a prominent feature of several of these strains, perhaps to a greater degree than is observed in human
sarcoglycanopathies. In the Sgca-null mouse, exons 2 and 3 and flanking introns of Sgca (the mouse
homologue of SGC, -sarcoglycan) were replaced by the neomycin resistance gene, creating a model of
LGMD2D (Duclos et al, 1998). The Sgca-null mouse has a phenotype of progressive muscular dystrophy
with histologic evidence of muscle necrosis and complete loss of the entire sarcoglycan complex and
sarcospan.
Via homologous recombination, exon 2 of murine -sarcoglycan was replaced by phosphoglycerate kinase
promoter/neomycin phosphotransferase cDNA (Hack et al, 1998). The resulting null mice displayed a
dystrophic myopathy and died prematurely of cardiomyopathy. There was complete loss of -sarcoglycan,
with secondary reductions in - and -sarcoglycan expression on immunohistochemistry.
Cardiomyopathy is also a hallmark of -sarcoglycan deficiency in mice and hamsters. Through
homologous recombination, exon 2 of -sarcoglycan was replaced by the neomycin resistance gene to
create Sgcd-null mice (Coral-Vazquez et al, 1999). Extensive pathologic disruptions were observed in the
skeletal muscles of these mice at an early age, as well as severe cardiomyopathy and histologic
abnormalities in the smooth muscle of the coronary vasculature. The naturally occurring BIO14.6 Syrian
hamster has a homozygous deletion in -sarcoglycan and develops a significant fatal cardiomyopathy but
only mild muscular dystrophy (Nigro et al, 1997; Roberds et al, 1993b; Sakamoto et al, 1997).
The naturally occurring myd mouse has an abnormal gait and dystrophic muscle histology. It was found to
have a frameshift deletion of exons 4-7 of the Large gene, which encodes a glycosyltransferase (Grewal
et al, 2001). Accordingly, the skeletal muscle has a secondary deficiency of -dystroglycan, while the
sarcoglycans and -dystroglycan remain intact.
A biglycan null mouse was recently generated by disrupting exon 2 of the bgn gene. Skeletal muscles
from these mice exhibit mild histologic abnormalities with secondary changes in the DAPC (Mercado et al,
2006).
Dogs
The xmd golden retriever is a naturally occurring dog model of DMD with absent RNA and protein
expression of dystrophin (Cooper et al, 1988). The genetic lesion is a point mutation that causes exon
skipping (Sharp et al, 1992). It more closely replicates the human phenotype than the currently available
mouse models, with marked elevations of CK, dystrophic findings on muscle histology, and clinical
weakness (gait difficulty) developing by age 8 to 10 weeks (Cooper et al, 1988; Kornegay et al, 1988;
Valentine et al, 1990). The xmd dog is also much closer to humans in size compared to the mdx mouse,
but is not as widely used in research studies due to the longer reproductive cycle and higher costs
associated with research involving these animals.
Zebrafish
In recent years, increasingly detailed investigations have been conducted of zebrafish (Danio rerio ) as
potential animal models for a number of diseases, including the muscular dystrophies. They have several
properties that distinguish them from mammalian models and contribute to their utility in the study of
muscle disease: short gestational periods, large litter sizes, and translucent bodies. Most components of
the DAPC have orthologues in zebrafish, and expression of the sarcoglycans, dystroglycan, and
dystrophin has been confirmed by immunoblotting (Chambers et al, 2001; Guyon et al, 2003b).
- 28 -
Several approaches have been used to create zebrafish models of human disease. One is mutagenesis
via immersion of male zebrafish in ethylnitrosurea followed by crossing with wild-type females, which
created a large number of mutant strains (Haffter et al, 1996). A phenotype screen of these mutants
yielded 166 strains with defects in embryonic motility, of which 63 (representing 18 distinct genes) also
had defects in skeletal muscle architecture (Granato et al, 1996). The mutation in one of these strains,
sapje (sap), was localized in dmd, the zebrafish homologue of human DMD (Bassett et al, 2003;
Bolanos-Jimenez et al, 2001). These fish exhibit progressive skeletal muscle degeneration due to
detachment of muscle fibers (Bassett et al, 2003).
A second approach to creating zebrafish models of disease is morpholino inhibition of target genes. This
has been performed on dystrophin (Guyon et al, 2003b), dystroglycan (Parsons et al, 2002), and
-sarcoglycan (Guyon et al, 2005). The resulting fish displayed decreased motility, and their spines were
bent or curved rather than straight (Fig. 216-4).
Dystrophin-null sapje mutant zebrafish (bottom) have patchy muscle birefringence at 7 days
postfertilization compared with wild-type zebrafish (top). Birefringence measures the amount of polarized
light that is rotated by highly ordered skeletal muscle. Patchy birefringence indicates muscle tearing in the
sapje mutant (Bassett et al, 2003). (Courtesy of J. Guyon and T. Pusack.)
These observations confirm that zebrafish can exhibit dystrophic phenotypes and be used as animal
models of muscular dystrophy, especially when large populations need to be studied.
- 29 -
Diagnosis
Serum Muscle Enzyme Measurements
Until the mid-twentieth century, muscular dystrophy was diagnosed entirely by clinical and pathologic
criteria. Aldolase, a glycolytic enzyme, was the first serum marker of muscular dystrophy identified (Sibley,
Lehninger, 1949). However, elevations in aldolase are also found in certain liver diseases and neoplasms
(Okinaka et al, 1961). The most specific serum marker for muscular dystrophy is creatine phosphokinase
(CPK or CK) (Ebashi et al, 1959; Okinaka et al, 1961). Several enzymes that are predominantly
expressed in liver are also found in muscle, but they are relatively nonspecific markers: alanine
aminotransferase (ALT, previously SGPT), aspartate aminotransferase (AST, previously SGOT), and
(lactate dehydrogenase (LDH) (Soltan, Blanchaer, 1959).
Measurements of serum markers, especially creatine phosphokinase and aldolase, are extremely useful
in screening patients with muscle weakness. An extremely high CK level (in the thousands of units per
liter) is highly suggestive of a muscular dystrophy (Dreyfus et al, 1960; Ebashi et al, 1959; Okinaka et al,
1961; Okinaka et al, 1959). Normal results or mild elevations (in the hundreds) may be consistent with a
handful of muscular dystrophies such as FSHD but often suggest another etiology. If the patient has true
proximal muscle weakness and depressed or absent reflexes, the possibility of spinal muscular atrophy
should be considered in the setting of normal or wildly elevated CK levels (type III, Kugelberg Welander, in
patients who are ambulatory). If the patient has no verifiable weakness, normal levels help to exclude the
possibility of muscular dystrophy.
In some cases, an asymptomatic or mildly symptomatic child with an undiagnosed case of muscular
dystrophy has liver enzymes tested for an unrelated medical issue, and may go through an evaluation for
hepatic disease when mild elevations in ALT, AST, and LDH are identified. It is important for general
pediatricians and pediatric gastroenterologists to remember that these enzymes may be mildly elevated in
cases of muscular dystrophy, and checking a creatine phosphokinase level in this situation may save the
child a prolonged evaluation.
Nerve Conduction Studies and Electromyography
Electromyography (EMG) is a useful diagnostic tool in many types of neuromuscular disorders, but it is
rarely used anymore in the evaluation of possible muscular dystrophies. The combination of muscle
enzyme measurements, genetic testing, and muscle pathology has formed a powerful diagnostic triad that
is extremely accurate. Before genetic testing and immunohistochemistry were developed, myopathic
findings on EMG were used to support the diagnosis of muscular dystrophy.
Genetic Testing
Genetic testing for many common and rare muscular dystrophies is becoming increasingly available from
a number of sources. The website http://www.genetests.org is a useful resource to determine whether
genetic testing is available for a particular disorder.
Relatively simple multiplex PCR amplification of "hotspot" exons, including 2 to 20 and 44 to 53, can
detect single-exon and multiexon deletions that are responsible for 65% of all cases of DMD and BMD
(Figs. 216-5 and 216-6) (Beggs et al, 1990; Chamberlain et al, 1988a; Chamberlain et al, 1991; Oudet et
al, 1992). Among the other mutations, 5% are duplications and 30% point mutations or small-scale
deletions or duplications (Galvagni et al, 1994; Hu et al, 1988; Hu et al, 1990; Roberts et al, 1994). The
DNA required for this testing can be extracted from blood lymphocytes. This has made the diagnostic
- 30 -
evaluation of muscular dystrophy much less invasive for those boys who present with a classic DMD or
BMD phenotype. If such a child has an elevated CK level and a positive genetic test, the diagnosis has
been established and muscle biopsy is not required unless the family and physician are interested in
quantifying the level of dystrophin expression in the muscle tissue in an attempt to refine the prognosis.
Typically, out-of-frame or nonsense mutations are associated with DMD, while in-frame mutations are
associated with BMD, but there are exceptions to this rule (Hu et al, 1992; Malhotra et al, 1988).
Schematic diagram showing the spectrum of deletions (thin bars) and duplications (thick bars) relative to
the position of exons in the mRNA and to the dystrophin molecule. Each bar represents the extent of the
deletion or duplication in a single patient. The hot spot for deletion around 45-52 is evident, as is the
collection of larger deletions found in the 5 half of the gene.
- 31 -
Agarose gel electrophoresis of multiplex polymerase chain reaction products from blood cell DNA of four
patients. Two multiplex reactions are shown. The first set of four lanes contains amplified products of
exons 48, 17, 8, and 44; the second set of four lanes contains amplified products of exons 45, 19, 25, 12,
and 4. In patient 1, exons 48-52 are deleted, and in patient 3, exons 45-52 are deleted. In patient 2 and in
two normal controls (...
It is a difficult situation when the genetic test is negative in a boy with weakness and an elevated CK level.
Some clinicians will request or perform a muscle biopsy at this point, whereas others will pursue
sequencing of the entire DMD gene in an attempt to spare the child a muscle biopsy. The advantage of
examining muscle pathology is that it casts a wide net and can detect evidence of a wide variety of muscle
and nerve disorders. The disadvantage is its invasive nature. The advantage of DMD sequencing is that it
is noninvasive, as it requires only DNA obtained from blood lymphocytes. However, it is currently
expensive, and it will not detect evidence for other disorders such as the LGMDs. This decision should be
made based on the level of clinical suspicion for DMD or BMD, and the availability of muscle biopsy and
pathology facilities.
Carrier testing of parents of affected patients is important. In cases of DMD or BMD, only the mother
typically requires analysis. This can be performed by laser densitometry or fluorescence in situ
hybridization (FISH) techniques (Allingham-Hawkins et al, 1998; Calvano et al, 1997). A complicating
factor in DMD/BMD genetics is the possibility that the mother may be a carrier with germ-line mosaicism,
and thus testing of DNA obtained from blood leukocytes or other somatic cells will not reveal the mutation.
Thus, when the mother tests negative as a carrier, the brother of a DMD/BMD patient who inherits the
same X chromosome as his brother has a 10 to 30% chance of also developing DMD/BMD (Bakker et al,
1989c; Bullock et al, 1996; Grimm et al, 1994; van Essen et al, 1992). Prenatal testing should be
considered even when the mother does not initially appear to be a carrier (Bakker et al, 1989a; Bakker et
al, 1989b). Fetal cells may be obtained for analysis using amniocentesis or by extracting fetal nucleated
erythrocytes from maternal blood samples (Sekizawa et al, 1996). Preimplantation diagnosis can help
- 32 -
screen for unaffected embryos at the very beginning of gestation (Grifo et al, 1994; Kristjansson et al,
1994; Liu et al, 1995).
Carrier testing is also possible in other muscular dystrophies such as merosin-deficient congenital
muscular dystrophy, using methods such as linkage analysis (if only the linkage region is known),
mutation analysis (if the gene is known and the mutation has been identified in the proband), and
expression analysis (if protein expression is detectable and reliable) (Guicheney et al, 1998; Naom et al,
1997a; Naom et al, 1997b; Voit et al, 1994).
Occasionally, an asymptomatic female may present with an elevated CK level. The most likely explanation
is that she is a carrier for DMD or BMD, and it may be worth performing genetic testing before pursuing a
muscle biopsy.
More recently, PCR primers designed to operate under the same conditions for all 79 exons of DMD have
been developed. These primers generate amplicons approximately 1000 bp in length. Internal primers are
then used for sequencing (Flanigan et al, 2003). An alternative approach uses automated primer design
tools to extend this to other genes involved in muscular dystrophy (Bennett et al, 2004). Clinical
implementation of these techniques will further refine the diagnostic accuracy of the muscular dystrophies.
This is a sorely needed advance, as the rate of misdiagnosis or absence of a molecular diagnosis for the
muscular dystrophies remains disturbingly high nearly two decades after the gene for DMD was cloned
(Griggs, Bushby, 2005; Schwartz et al, 2005).
Muscle Pathology
The pathologic diagnosis of the muscular dystrophies was not very specific before the DMD gene was
cloned in 1986, since the biochemical defect was not previously known. Standard histochemical stains
such as hematoxylin and eosin demonstrated infiltration of inflammatory cells, necrosis, regeneration of
fibers, and, in the later stages, replacement of muscle fibers with connective and adipose tissues (Figs.
216-7 and 216-8). These changes are suggestive of muscular dystrophy but do not provide any indication
of the subtype. Additionally, some cases of inflammatory myopathy may resemble some cases of
muscular dystrophy in basic histology, and conversely, also detracting from the utility of basic
histochemical stains in isolation.
- 33 -
Cryostat section of an early-stage DMD muscle biopsy. Several necrotic fibers undergo phagocytosis.
There is an abnormal variability of the muscle fiber size but relatively little endomysial connective tissue
excess (modified trichrome stain; 350).
Cryostat section of an advanced-stage DMD muscle biopsy. A group of necrotic and regenerating muscle
fibers is apparent. In addition, there is a marked variability of fiber size and conspicuous excess of
endomysial connective tissue (modified trichrome stain; 350).
- 34 -
After the protein product, dystrophin, was identified, antibodies against various portions of the protein
were developed and used with fluorescence or radioactive isotopes to quantify (immunoblots, also known
as Western blots) and localize it (immunohistochemistry) within the muscle fiber. Clinically, immunoblots
and immunohistochemical stains could be used to determine the presence or absence of dystrophin within
the muscle and thus provide a means of diagnosis at a time when DNA sequencing was still a laborious
and difficult process (Fig. 216-9) (Arahata et al, 1988; Bonilla et al, 1988; Zubrzycka-Gaarn et al, 1988). In
most cases of DMD, dystrophin is virtually undetectable (less than 3% of normal levels) on immunoblot
analysis, while in BMD dystrophin is present at 40 to 100% of normal levels but typically has an abnormal
molecular weight (Fig. 216-10) (Arahata et al, 1989; Hoffman et al, 1988a). Manifesting female carriers will
have a partial deficiency of dystrophin (Fig. 216-11).
A, B, Transverse cryostat sections of muscle showing immunoreactive dystrophin using a monoclonal

antibody recognizing rod-domain epitopes. The bound antibodies are displayed by peroxidase reaction. A,
Normal muscle. B, Muscle from DMD patient. C, D, Serial sections from a DMD muscle biopsy. C,
Antidystrophin antibody as in A and B displayed by CI3 fluorochrome. D, Antiutrophin monoclonal
antibody for the N-terminus. In C, "revert...
- 35 -
Immunoblot (left) showing normal-sized 427-kDa dystrophin from a normal muscle biopsy (N) and a
lower-molecular-weight dystrophin in reduced amount from a BMD patient (B). Muscle biopsy from the
same BMD patient (right) shows weak and interrupted dystrophin immunoperoxidase staining (350).
Dystrophin immunofluorescence from a manifesting carrier showing a cluster of dystrophin-negative

muscle fibers that had normal spectrin and laminin immunostaining (350).
In recent years, antibodies to a number of other muscle proteins have been developed, including the
sarcoglycans, merosin, and emerin, enabling pathologists to stain muscle samples with a panel of
antibodies to narrow the diagnostic possibilities (Figs. 216-12, 216-13, and 216-14). To interpret a pattern
of immunohistochemical stains, it is important to be familiar with the interactions between proteins. A
deficient pattern of staining in one protein does not always imply that the corresponding gene is
responsible for the dystrophy.
- 36 -
Immunostaining with antibody against -sarcoglycan in muscle sections from (A) a 13-year-old boy who
presented with a Duchenne-like muscular dystrophy and (B) a normal control. The patient was shown to
have a missense mutation in the -sarcoglycan gene, resulting in failure to integrate into the complex.
Immunostaining with antimerosin antibody of muscle from (A) merosin-deficient patient with congenital
muscular dystrophy and (B) normal control. In the patient muscle, a few fibers retain some
immunoreactive merosin (350).
- 37 -
Immunostaining with antiemerin antibody of muscle from (A) normal control and (B) a patient with
Emery-Dreifuss muscular dystrophy. In the control tissue, emerin is localized to the membrane of
myonuclei (350).
In DMD, there is a secondary deficiency of the dystroglycans and sarcoglycans and normal merosin
staining (Ohlendieck et al, 1993). In another example, a mutation in a sarcoglycan gene will typically
cause not only an absence of staining for the corresponding protein, but also partial deficiencies in one or
more of the other sarcoglycans. This occurs most consistently in - and -sarcoglycanopathy (Vainzof et
al, 1996). The secondary effects of - and -sarcoglycanopathies on the other sarcoglycans and
sarcospan are less consistent, and sometimes there may be no secondary biochemical effects at all
(Crosbie et al, 1997; Crosbie et al, 2000). Primary -sarcoglycanopathy may in some cases be
accompanied by secondary deficiencies in - and -sarcoglycans (Barresi et al, 1997). Dystrophin staining
is usually normal in the sarcoglycanopathies (Ljunggren et al, 1995). In light of these secondary effects,
immunohistochemical analysis of the sarcoglycans in muscle specimens obtained for diagnostic purposes
should include all four for a proper interpretation. A diagnosis of an inherited disorder such as muscular
dystrophy is never completely established unless a mutation is found in a causative gene. The interactions
among various muscle proteins raise the possibility that in the future, synergistic heterozygosity will be
found to cause rare cases of muscular dystrophy in which traditional mutations are not identified. This
phenomenon arises from partial defects at multiple points in a pathway, and has been postulated to occur
in some metabolic muscle disorders (Vockley et al, 2000).
- 38 -
Therapies
Because it is by far the most common muscular dystrophy, DMD has received the most attention for
therapeutic studies, whether performed in vitro, in animal models, or in human clinical trials. The therapy
for DMD is the most highly developed. Therapies for other muscular dystrophies are largely derived from
experience with DMD. Despite the significant advances in supportive therapies, including surgeries and
mechanical ventilation, DMD remains a fatal disease, and intense and diverse efforts to find a cure remain
quite active.
Patients and their families should be warned of two potentially serious acute muscular complications of
certain myopathies that require emergency medical evaluation: malignant hyperthermia and
myoglobinuria/rhabdomyolysis. Primary malignant hyperthermia is a separate disease category,
associated with mutations in various genes, most prominently RYR1, the ryanodine receptor (MacLennan
et al, 1990; McCarthy et al, 1990). Secondary malignant hyperthermia may occur in association with
certain myopathies, most commonly central core disease (also associated with mutations in RYR1), but
also with muscular dystrophies and other muscle disorders. This condition is typically triggered by specific
anesthetic agents, most notably succinylcholine and halothane; inhaled agents other than halothane
should also be avoided. The syndrome is potentially fatal and is characterized by severe muscle rigidity,
myoglobinuria/rhabdomyolysis, hyperthermia, and hyperkalemia. Dantrolene is the key therapy;
supportive treatment of the myoglobinuria/rhabdomyolysis, hyperthermia, and hyperkalemia are also
critical for survival. Myoglobinuria/rhabdomyolysis in isolation may also occur in muscle disorders and may
be triggered by environmental stressors such as high or low temperatures, excessive exercise, infection,
toxins, alcohol, and trauma. Any electrolyte imbalances associated with this condition should be treated
immediately, and intravenous fluids will often be required to prevent kidney damage.
Without any specific therapy, the life expectancy of a child with DMD does not typically extend beyond the
second decade of life. However, supportive therapies have significantly improved the quality of life and life
expectancy, to the point where most patients survive well into their third and sometimes even fourth
decade (Eagle et al, 2002). New therapies have been developed to reduce the impact of both the
pulmonary and cardiac complications, by far the most common causes of death in affected children. Aside
from a pediatric neurologist, other physicians frequently involved in the care of a child with DMD include
an orthopedic surgeon, pulmonologist, and cardiologist. Physical therapists also contribute a great deal to
the care of these children.
Steroid Therapy
Prednisones potential as a therapy for DMD was first raised in a pilot study of 14 patients that was
published in 1974 (Drachman et al, 1974). This approach was somewhat controversial, and the very
obvious side effects of prednisone made it difficult to conduct a blind, placebo-controlled trial, although a
placebo-controlled trial without blinding was feasible. Because a large number of DMD patients follow a
predictable course, some investigators in the 1970s and 1980s began to establish a baseline natural
history against which therapeutic trials could be measured (Mendell et al, 1987). A clinical trial of
prednisone in 33 boys affected by DMD was conducted using these natural history controls,
demonstrating improvement in strength over a 6-month period (Brooke et al, 1987).
The first long-term trial of prednisone, at a dose of 2 mg/kg per day in 16 affected boys, demonstrated that
the mean age of loss of ambulation could be delayed from 10 years (range, 7-13 years) to 12 years, a
significant gain in quality of life (DeSilva et al, 1987). A larger trial divided 103 boys with DMD into three
treatment groups: 1.5 mg/kg per day prednisone, 0.75 mg/kg per day prednisone, and placebo. The boys
in both prednisone groups experienced significant improvements in multiple measures of strength and
- 39 -
function over the 6-month trial period, suggesting that the lower dose may be sufficient (Mendell et al,
1989). A trial involving 93 affected boys demonstrated that a dose of 0.75 mg/kg per day was efficacious
(Fenichel et al, 1991a). Since then, several randomized, controlled clinical trials lasting 6 to 18 months
have been conducted, confirming an optimal prednisone dose of 0.75 mg/kg per day (maximum, 60-80
mg/d) to improve motor strength and pulmonary function (Griggs et al, 1991; Griggs et al, 1993).
Deflazacort has been explored as an alternative steroid to prednisone (Angelini et al, 1994; Mesa et al,
1991; Reitter, 1995). At a dose of 0.9 mg/kg per day, it provides similar benefits, with one small study
demonstrating milder side effects than prednisone (Bonifati et al, 2000).
Steroid therapy has become increasingly accepted as an efficacious therapy for DMD and potentially for
other muscular dystrophies. However, a trial in FSHD did not demonstrate a beneficial effect (Tawil et al,
1997), and thus steroids are not routinely used in other forms of muscular dystrophy.
Unfortunately, side effects of steroid therapy are numerous and potentially severe. Reported side effects
in DMD patients treated with prednisone include weight gain, stress fracture due to osteopenia,
hyperactivity and other behavioral changes, gastritis, hypertension, cataracts, and
hyperglycemia/glycosuria (DeSilva et al, 1987; Fenichel et al, 1991a). The effect of the weight gain is
unclear, as some of the additional weight may be a result of increased muscle mass, but excessive weight
gain due to adipose tissue may be counterproductive by increasing the load borne by the musculoskeletal
system without improving strength. Osteopenia increases the risk of fractures in children who already fall
more frequently than their peers.
To reduce the incidence and severity of steroid side effects, variations on the standard regimen have been
studied, including ones involving lower doses (0.3 mg/kg per day) and ones in which the steroids are not
administered on a daily basis. Common schedules include every-other-day dosing, which initially
appeared to be less efficacious and to carry the same side effect risks as daily dosing (Fenichel et al,
1991b). These schedules provide slightly less efficacious therapy but do alleviate the side effects. More
thorough evaluations of various alternate regimens are needed (Moxley et al, 2005).
The mechanism of action of steroids in the setting of DMD is not entirely clear, although the
anti-inflammatory effect appears to contribute. Prednisone was demonstrated to increase dystrophin
expression in myoblast cultures (Sklar, Brown, 1991), but this could not be confirmed in pre- and
posttreatment muscle biopsies in humans (Burrow et al, 1991). A decrease in inflammatory activity was,
however, noted in human muscle biopsies, suggesting that the anti-inflammatory properties of prednisone
are key to its efficacy (Kissel et al, 1991). The immunosuppressive effect does not appear to be the
primary mechanism of action (Kissel et al, 1993). In cell culture, steroids promote various aspects of
myogenesis (Passaquin et al, 1993), including the fusion of myoblasts (Metzinger et al, 1993) and
prevention of myotube death (Sklar, Brown, 1991). Steroids have also been shown to alleviate myofiber
damage in rats (Jacobs et al, 1996). Metabolic studies in humans suggest that steroids improve muscle
mass by inhibiting proteolysis (Rifai et al, 1995).
-Agonist Therapy
Administration of albuterol has been shown to increase muscle mass and some measures of strength in
patients with facioscapulohumeral muscular dystrophy, but the improvement overall was not dramatic
(Kissel et al, 1998; Kissel et al, 2001).
- 40 -
Supportive Management
There are a number of orthopedic and orthotic interventions that apply to DMD. The one that perhaps has
had the greatest impact is scoliosis surgery. Scoliosis is a complication that typically accelerates after the
child begins sitting in a wheelchair for long periods of time. Not only does scoliosis cause discomfort and
social embarrassment due to postural changes, but the imbalances in lung volumes increase the
likelihood of developing atelectasis, resulting in reduced lung capacities and more frequent episodes of
pneumonia. The scoliosis surgery stabilizes the spine and enables the child to breathe more normally,
reducing the impact of potentially fatal pulmonary complications.
Due to the high risk of pneumonias and respiratory compromise in advanced cases, affected children will
need to have their lung function monitored with pulmonary function testing (PFTs), and a pulmonologist
should be consulted. Respiratory infections should be treated more aggressively than in unaffected
children, and the threshold for hospital admission should be lower for such complications.
Various options for mechanical ventilation have been explored over the past several decades, and its use
has become routine in the later stages of the disease. A number of studies have suggested that
mechanical ventilation prolongs life expectancy, including two recently published retrospective
observations covering several decades (Eagle et al, 2002; Jeppesen et al, 2003). A less invasive
alternative method, nocturnal nasal ventilation, may be helpful in selected patients (Guilleminault et al,
1998; Simonds et al, 1998).
The cardiac complications of the muscular dystrophies include cardiomyopathy and arrhythmias.
Previously, no specific therapy was available for these complications, and thus routine monitoring of
asymptomatic individuals was not common. However, interventions have become more sophisticated,
including the use of ACE inhibitors and beta blockers for cardiomyopathy. Thus, patients newly diagnosed
with a muscular dystrophy are now commonly referred for a baseline cardiac evaluation, including
electrocardiography and echocardiography, and followed at increasingly frequent intervals as the disease
progresses (Bushby et al, 2003). However, there is some disagreement about the utility of monitoring
asymptomatic individuals (English, Gibbs, 2006). Cardiac transplantation is generally not feasible in DMD
but may be a consideration in selected cases of BMD (Bushby et al, 2003; English, Gibbs, 2006).
When heel cord contractures develop, the least invasive therapies include stretching exercises under the
guidance of a physical therapist. In more severe cases, the exercises may be supplemented by orthotic
devices such as molded ankle-foot orthoses (MAFOs) or night casts. In the most severe cases, especially
when the contractures limit the ability of the patient to walk, heel cord lengthening surgery may be
beneficial. However, this surgery is not a permanent solution, and over time the contractures may worsen
again.
Mild to moderate mental retardation is a frequent, though not universal, complication of DMD. Autistic
spectrum phenotypes also have been observed in cases of DMD and occur with a greater frequency than
in the background population (Wu et al, 2005). Children with DMD should in general not be placed in
special education settings based on their physical disabilities alone, but if cognitive or behavioral
disabilities are significant, such programs may be appropriate for certain children.
The overall goal of therapy is to maintain mobility as long as possible. Within reasonable limits, exercise
and physical activity are beneficial, and affected children should be encouraged to remain active within
their families and communities.
- 41 -
Experimental Therapies
As soon as the DMD gene was cloned, scientists and physicians began to envision genetically targeted
therapies for the disease. Over the past two decades, a number of approaches have been studied that
propose different solutions to four key issues: what variant of DMD to insert, what vector to use, whether
to use cell-based or non-cell-based approaches (and if so, what type of cell), and mode of delivery.
Direct gene therapy was explored early. In one set of experiments, full-length murine dystrophin cDNA
was attached to an M-creatine kinase promoter enhancer region and then directly injected into mdx
mouse zygotes (Cox et al, 1993).
Gene Therapy
The use of viral vectors has been explored extensively. Their use is complicated by the enormous size of
the DMD gene. Full-length DMD will not fit in most viral vectors. Researchers developed truncated
dystrophin constructs that could fit into a viral vector (Acsadi et al, 1991) and correct some of the
pathologic features of dystrophin deficiency in mdx mice (Wells et al, 1992). Adenovirus has been the
easiest vector to work with due to its efficient delivery system (Graham et al, 1977). Expression of a
Becker minigene has been demonstrated in mdx mice (Acsadi et al, 1996; Clemens et al, 1995; Ragot et
al, 1994), -sarcoglycan in the BIO 14.6 hamster (Holt et al, 1998), and -sarcoglycan in a knockout
mouse (Duclos et al, 1998). However, the duration of expression was brief in all of these experiments.
Adeno-associated virus (AAV) has shown promise as an alternative vector. It is much smaller than
adenovirus and is less prone to triggering an immune response in the host (Xiao et al, 1996). The main
drawback is its limited capacity of 5 kb; the human dystrophin cDNA is 14 kb long. For this reason, one of
the first muscular dystrophy genes replaced using this vector was SGCD (-sarcoglycan), a smaller gene
that was delivered by intramuscular injection to the BIO14.6 dystrophic hamster with restoration of
histologic structures (Li et al, 1999) and functional recovery of muscle (Xiao et al, 2000). Administration of
AAV carrying SGCD into the coronary arteries of the BIO14.6 hamster resulted in histologic improvement
of the cardiac muscle (Li et al, 2003). More recently, intraperitoneal delivery of AAV-8 containing SGCD
into TO-2 hamsters, which are derivatives of the BIO14.6 strain, led to histologic and functional recovery
of both skeletal and cardiac muscle (Zhu et al, 2005).
In an attempt to address dystrophin deficiency using the AAV vector, several minidystrophin genes
smaller than 4.2 kb were constructed and delivered to mdx mice (Wang et al, 2000). Two of the
constructs, 3849 and 3990, were able to restore the DAPC architecture on a histologic level. Other
truncated dystrophin constructs, more recently termed microdystrophins, also have been studied in the
context of the AAV vector. Delivery of a R4 microdystrophin to the heart of a newborn mdx mouse
produced restoration of the DAPC in the heart (Yue et al, 2003). Another construct, CS1, was injected
into the tibialis anterior muscles of mdx mice, which were found to have improved force generation
(Yoshimura et al, 2004). Intramuscular injections of AAV-5 containing a R4/C microdystrophin were
more effective in young rather than adult mdx mice; the young mice displayed some histologic and
functional improvements in the injected muscles (Liu et al, 2005). Intramuscular injections of AAV-6 vector
containing the H2-R19 minidystrophin gene led to moderate functional improvement (Lai et al, 2005).
Systemic injection of AAV pseudotype 6 vector containing R4-23/CT microdystrophin into the tail vein
of mdx mice resulted in widespread expression of the microdystrophin in skeletal muscles, with some
functional improvement (Gregorevic et al, 2004).
- 42 -
Cell-Based Therapies
Restoration of DMD expression via cell-based therapies has been explored extensively since the late
1980s. One approach adapts the muscles ability to repair itself using satellite cells, which are muscle
precursor cells found between the sarcolemmal and basement membranes of muscles (Seale, Rudnicki,
2000). In one experiment, dystrophin expression was induced by direct injection of muscle precursor cells
into affected muscles of the mdx mouse (Partridge et al, 1989). When a similar approach was studied in
human patients with DMD, dystrophin expression was detected (Gussoni et al, 1992), but improvements
in strength found in a very small sample size were only transient (Huard et al, 1992a) and the overall
results were judged to be poor (Karpati et al, 1993a; Mendell et al, 1995; Miller et al, 1997; Tremblay et al,
1993). Further examination of muscle tissue from study subjects suggested that incomplete fusion of
myoblasts with host muscle fibers contributed to the unsatisfactory outcome (Gussoni et al, 1997; Gussoni
et al, 1996).
It then became apparent that the mononuclear cell population in muscle was heterogeneous and that
different subpopulations might have greater myogenic potential than others (Beauchamp et al, 1999; Qu
et al, 1998). Further research was directed at devising techniques for segregating these subpopulations
and identifying which ones had the greatest myogenic potential.
Bone marrow-derived mesenchymal cells are recruited to assist in skeletal muscle repair after injury,
suggesting that a subpopulation of these cells has myogenic potential (Cossu, 1997; Ferrari et al, 1998).
Bone marrow transplantation in mdx mice resulted in the presence of bone marrow-derived cells within
skeletal muscle (Bittner et al, 1999).
Muscle is also a potential source of precursor cells. A subpopulation of hematopoietic stem cells shared
the ability to expel Hoechst 33342 dye at a high rate, enabling them to be isolated from other
hematopoietic stem cells (Goodell et al, 1996). This technique was adapted to isolate a side population
(SP) of muscle-derived cells (Fig. 216-15) (Gussoni et al, 1999) that demonstrate multilinear engraftment
in mice (Jackson et al, 1999) and promote bone healing (Lee et al, 2000). When injected intravenously
into mdx (Gussoni et al, 1999) and mdx 5cv (Bachrach et al, 2004) mice, these SP cells partially restored
dystrophin expression in skeletal muscle.
- 43 -
Immunostaining of cultured side population (SP) and main population (MP) cells derived from mouse
muscle. Cultured SP cells stain positive for the chemokine receptor CXCR4 (arrows) using two
monoclonal antibodies: (A) 12G5 conjugated to phycoerythrin (PE) and (C) 2B11 conjugated to
fluorescein isothiocyanate (FITC). In contrast, cultured MP cells do not express CXCR4 (B and D).
(Courtesy of E. Bachrach and E. Luth.)
There are other potential sources of muscle precursor cells, including umbilical cord blood, peripheral
blood, and brain (Bjornson et al, 1999; Clarke et al, 2000; Lu et al, 1996).
The optimal mode of delivery has been controversial, and this issue has been complicated by the choices
made to address the other issues above. Intramuscular and intravenous injections have been most
commonly used. The disadvantage of intramuscular injections is the limited diffusion capacity of DNA,
viruses, or muscle precursor cells within the muscle itself outside the vasculature. Intravenous injections
allow for more diffuse seeding of the muscle, but the disadvantage, especially with cell-based therapies, is
that the cells will be filtered by the lungs, reducing the number that reach the skeletal muscles themselves.
An alternative mode of delivery is via intra-arterial injections directly into the iliac artery (mice) or femoral
artery (humans). The former has been attempted in -sarcoglycan-deficient mice (Sampaolesi et al, 2003)
and mdx 5cv mice (Bachrach et al, 2006) with promising results.
- 44 -
Exon Skipping
Another genetic approach to treating genetic disorders involves exon skipping, or inducing the
transcriptional mechanism of the nucleus to skip over a particular exon. This may be achieved by
administering 2-O-methyl antisense oligoribonucleotides that bind to the splice site of the targeted exon
(Dominski, Kole, 1993). When a frameshift or nonsense mutation is present in an exon, this intervention
can enable the cell to produce a mildly truncated but functional protein rather than a severely truncated
protein that becomes degraded or is nonfunctional. Exon 23 of the murine version of DMD in the mdx
mouse was targeted in this manner via intramuscular injections, producing intact production and
localization of dystrophin in muscle fibers (Mann et al, 2001). Further study of mice treated in this fashion
demonstrated functional improvement in muscle strength (Lu et al, 2003). Systemic injection of these
oligonucleotides into the tail vein of mdx mice demonstrated restored dystrophin expression in skeletal
muscles, but at widely varying levels, and there was no uptake at all in the heart (Lu et al, 2005). Systemic
intravenous delivery of an alternative morpholino oligonucleotide in mdx mice also produced a wide range
of expression levels among skeletal muscles, but pathologic and functional improvement was observed
(Alter et al, 2006).
Myostatin Inhibition
Myostatin, also known as growth/differentiation factor 8, is an inhibitor of muscle growth that has been
studied for some time (McPherron et al, 1997). Mice (McPherron et al, 1997; Zhu et al, 2000) and cattle
(Grobet et al, 1997; Grobet et al, 1998; Kambadur et al, 1997; McPherron, Lee, 1997) with mutations in
the myostatin gene were noted to have dramatically increased muscle mass. Inhibition of myostatin in
wild-type (Whittemore et al, 2003) and mdx (Bogdanovich et al, 2002) mice via intraperitoneal injection of
monoclonal antibodies resulted in increased muscle mass and strength. To date, only one human has
been found to have a naturally occurring mutation in myostatin (Schuelke et al, 2004). A boy, last
examined at 4.5 years, had a homozygous splice-site mutation in the myostatin gene, with a phenotype of
increased muscle mass and motor strength (Schuelke et al, 2004). It was especially encouraging that at
that age, he had not developed any theoretical complications of myostatin deficiency, especially
hypertrophic cardiomyopathy; however, further observation of this child over time will provide more
important information about the effects of myostatin deficiency in humans.
Conclusion
The scientific and clinical advances in the muscular dystrophies over the past several decades have been
remarkable, with important discoveries in the genetic, biochemical, and therapeutic aspects of the field. A
precise molecular diagnosis of a large number of muscular dystrophies is now possible, and therapeutic
refinements have dramatically increased the life expectancy and quality of life in affected individuals.
Many of these patients and their families have great hopes that new therapies will eventually halt or even
reverse the progression of these diseases. Through a variety of approaches, including the ones outlined
above, scientists and physicians are making great efforts to fulfill those hopes.
Acknowledgments
The current authors are indebted to Ronald G. Worton, Maria Judit Molnar, Bernard Brais, and George
Karpati, authors of the previous version of this chapter. We have used a number of their figures, as well as
selected text and references. The authors are supported by NIH P01 NS40828-01A1 (L.M.K.), NIH K08
NS048180 (P.B.K.), the Bernard F. and Alva B. Gimbel Foundation (L.M.K.), and the Joshua Frase
Foundation (L.M.K.). L.M.K. is an Investigator at the Howard Hughes Medical Institute.
- 45 -
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Chapter 216: The Muscular Dystrophies

PART 25: MUSCLE

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Chapter 216: The Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies

Duchenne (OMIM No.

Severe, progressive muscle

Becker (OMIM No.

Mild form, onset after age 16, muscle

Limb-Girdle (OMIM: see

Severity variable, overlap DMD and

Hypotonia, joint contractures, general

Common only in Japan, similar to

Contractures of elbow, neck, and spine,

Eyelid ptosis and dysphagia, onset after

Facial and shoulder weakness, scapular

NOTE: AR = autosomal recessive; AD = autosomal dominant.

Table 216-2: Cellular Localization of Proteins Involved in the Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies

Clinical Presentation and Natural History: Dystrophinopathies

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Chapter 216: The Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies

Duchenne Muscular Dystrophy/Becker Muscular Dystrophy Carriers

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Chapter 216: The Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies

LGMD2C-F: The Sarcoglycanopathies

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Chapter 216: The Muscular Dystrophies

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Chapter 216: The Muscular Dystrophies