Muscular dystrophies are an inherited group of primary diseases
of muscle, characterized pathologically by muscle fiber degeneration and
clinically by progressive muscle weakness. Pathologic, clinical and
genetic criteria have been used as the basis for their classification.
Muscular Dystrophies (Dystrophinopathies)
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy
(BMD) are progressive myopathies, inherited as X-linked recessive
traits. DMD is the most common form of muscular dystrophy, with
an incidence of about 1 in 3300 live male births and a prevalence
rate in the total population of about 3 per 100,000. BMD has a similar
presentation but a relatively milder clinical course. The reported
incidence of BMD has varied from about 1 in 18,000 to 1 in 31,000
male births. In addition, there is an intermediate group of patients
with either mild DMD or severe BMD, who are known as outliers. It
is now well known that all 3 types of muscular dystrophy are allelic,
resulting from dystrophin deficiency due to mutations of a single
gene, called the dystrophin gene.1
Other dystrophinopathies, occurring at a lower incidence, include:
- manifesting DMD/BMD carrier females,
- X-linked dilated cardiomyopathy, and
- muscle cramps with myoglobinuria.
Great heterogeneity in the clinical features and course of the
various dystrophinopathies has been observed, creating a spectrum
ranging from very mild to very severe presentations. The severe
end of the spectrum includes DMD, BMD the outliers or intermediate phenotype
in which skeletal muscle is primarily affected, and X-linked dilated
cardiomyopathy in which the heart is the organ primarily affected.
Females who carry DMD/BMD can be totally asymptomatic or
can manifest mild to severe symptoms.
Clinically, the distinction between DMD and BMD is made by the
age of wheelchair confinement, which is less than 13 years in DMD
and beyond 16 years in BMD. Patients who become wheelchair-bound
between 13 years and 16 years are classified as outliers or as exhibiting
an intermediate presentation. The outlier group could be classified clinically
as having either mild DMD or severe BMD.
In children with Duchenne muscular dystrophy (DMD), although there
is histologic and laboratory evidence of myopathy from birth, the
onset of weakness usually occurs between 2 and 3 years of age; it
may be delayed and become apparent after the age of 3 years, but almost
all patients with DMD become symptomatic before age 5 years. The
child usually has difficulty with running, jumping, going up steps,
and other similar activities; an unusual waddling gait, lumbar lordosis,
and calf enlargement are usually observed. Muscular weakness is
symmetrical and selectively affects proximal limb muscles before
distal and the lower extremities before the upper. Early on, the
patient may complain of leg pains. Jumping and running are almost
impossible in most cases, and, in arising from the floor, affected
boys use hand support to push themselves to an upright position
(Gower sign). Neck flexor weakness occurs at all stages of the disease
and distinguishes boys with DMD from patients with milder presentations;
at least early on, patients with BMD and outliers appear to have
preserved neck flexor strength. Cardiac muscle is also affected.
Most children with DMD often have varying degrees of nonprogressive
impairment of cognitive function, although an occasional child may
have average or above-average intelligence. Earlier reports suggested
that verbal IQ was more affected than performance IQ. Recently,
however, a more specific cognitive profile has emerged, demonstrating
deficits in working memory and executive function.
Physical examination shows pseudohypertrophy of the calf muscles
(Fig. 572-1) and, in some instances, of quadriceps,
gluteal, deltoid, and other muscles, and lumbar lordosis, waddling
gait, shortening of the Achilles tendons, and hyporeflexia or areflexia.
The shortening of the Achilles tendons leads to toe walking.
Pseudohypertrophy of the calf muscles in a patient with
Duchenne muscular dystrophy.
(Courtesy of Theodore Munsat, MD, New England
Medical Center, Boston MA. Reprinted from: Darras BT, Menache CC,
Kunkel LM. Dystrophinopathies. In: Jones HR Jr, De Vivo DC, Darras
Neuromuscular Disorders in Infancy, Childhood,
and Adolescence: A Clinician’s Approach. Philadelphia,
PA: Butterworth-Heinemann; 2003:649; with permission
Between 3 and 6 years of age, there may be some evidence of transient
improvement, known as the “honeymoon phase” of
muscular dystrophy; this is gradually followed by relentless deterioration,
leading to wheelchair confinement by the age of approximately 13
years. Wheelchair-bound children tend to develop contractures and
scoliosis, with deterioration of pulmonary function. The incidence
of cardiomyopathy increases gradually in teenage years, with about
one third of patients being affected by age 14 years, one half by
age 18 years, and all patients after age 18 years. Intestinal hypomotility,
also known as intestinal pseudo-obstruction, is an important and sometimes
life-threatening complication in patients with Duchenne muscular
dystrophy (DMD). It may present with acute gastric dilatation, vomiting,
and abdominal pain and distention and seems to be related to smooth
muscle degeneration. Most patients with DMD die in their late teens
or twenties (mean: 20 Â± 3.9 years) from respiratory insufficiency
or from cardiac failure secondary to progressive cardiomyopathy
(10–40%). In some, the immediate cause of death
is not apparent.2 Assisted ventilation can prolong life
expectancy, but the patient will be dependent for activities of daily
In Becker muscular dystrophy, the age of onset of symptoms is
usually later, between the ages of 5 and 15 years (mean: approximately
12 years) or sometimes even in the third or fourth decade or later,
and the degree of clinical involvement is milder; cardiac disease
and cognitive impairment are not as common or as severe as in the
Duchenne variety, and gastrointestinal symptoms are essentially
absent. Also, contractures and scoliosis are not as likely to develop
in BMD. In addition, in Becker and intermediate types of muscular dystrophy,
neck flexor muscle strength is relatively well preserved. Patients
with BMD typically remain ambulatory beyond the age of 16 years
and into adult life; they usually survive beyond the age of 30 years,
with death from respiratory failure or cardiomyopathy/cor
pulmonale usually occurring between 30 and 60 years.3 Mean
age at death is in the mid-40s. Serum creatine kinase levels are
usually markedly increased in Becker dystrophy and, therefore, cannot
be used as a way of differentiating between the 2 types of dystrophy.
Duchenne Muscular Dystrophy (Dmd)/Becker Muscular Dystrophy
(Bmd) Carrier Females
Carriers are usually free of symptoms (DMD, 76%; BMD,
81%) but may have mildly increased serum creatine kinase
and usually mild calf hypertrophy. However, 8% to 19% present
with mild to moderate, but occasionally severe, muscle weakness
of the limb-girdle type or even with DMD/BMD.
The DMD/BMD gene, now known as the dystrophin gene,
is the largest gene yet identified in humans, spanning approximately
2.3 megabases on the short arm of the X chromosome at Xp21.1 The
protein product dystrophin has a total molecular weight of 427 kilodaltons
(kD) and is recognized on Western blots of human skeletal muscle
proteins using antidystrophin antibodies.4 With
the use of immunocytochemistry, dystrophin has been localized to
the cytoplasmic face of the plasma membrane of muscle fibers. It
has also been shown that dystrophin is part of a large, tightly
associated glycoprotein complex containing many other proteins (Fig. 572-2). It is believed that in normal
cells, the dystrophin stabilizes the glycoprotein complex and protects
it from degradation; in the absence of dystrophin, the complex becomes
unstable. There is almost always secondary reduction in the amount
of proteins of the glycoprotein complex in the muscle tissue of
patients with DMD. The loss of associated membrane proteins as a
result of dystrophin deficiency may initiate the degenerative changes
seen in muscular dystrophy.
The dystrophin-associated protein complex. Arrows indicate
the protein components mutated in various muscular dystrophies.
The laminin a2-chain gene is mutated in a subtype of congenital
muscular dystrophy without structural brain anomalies and the sarcoglycan
proteins in patients with sarcoglycanopathies (autosomal recessive LGMDs).
BMD, Becker muscular dystrophy; CMD, congenital muscular dystrophy;
DMD, Duchenne muscular dystrophy; LGMD, limb-girdle muscular dystrophy. (Courtesy
K O’Brien and L Kunkel, Children’s Hospital Boston.
Reprinted from: Darras BT, Menache CC, Kunkel LM. Dystrophinopathies.
In: Jones HR Jr, De Vivo DC, Darras BT, eds. Neuromuscular Disorders
in Infancy, Childhood, and Adolescence: A Clinician’s Approach.
Philadelphia, PA: Butterworth-Heinemann; 2003:649;
with permission from Elsevier.)
Of the dystrophin gene mutations identified so far, most are
deletions, detected in approximately 65% of DMD patients
and 85% of BMD patients.1 Partial gene
duplications have also been reported in 6% to 10% percent
of patients. In the remaining patients without detectable deletions
or duplications, the molecular lesions represent small insertions/deletions,
point mutations, or splicing errors (Table 572-1).
Table 572-1. Molecular
Genetic Testing Used in the Dystrophinopathies ||Download (.pdf)
Table 572-1. Molecular
Genetic Testing Used in the Dystrophinopathies
|Test Method||Mutations Detected||Males with Duchenne muscular dystrophy (%)||Males with Becker muscular dystrophy (%)|
|Targeted mutation analysis (multiplex, polymerase chain reaction,
Southern blotting, or fluorescent in situ hybridization)||Deletion of 1 or more exons of DMD gene||~ 65||~ 85|
|Targeted mutation analysis (Southern blotting or quantitative
polymerase chain reaction)||Duplication of 1 or more exons of DMD gene||~ 6–10||~6–10|
|Mutation scanning and/or sequence analysis||Small insertions/deletions/point mutations/splicing
mutations of DMD gene||~ 25–30||~ 5–10|
Published studies have failed to reveal any apparent correlation
between the size of dystrophin gene deletions and the severity and
progression of the DMD/BMD phenotype. The molecular basis
of Duchenne versus Becker muscular dystrophy seems to be related
to the disruption or preservation of the amino acid reading frame by the deletion
mutations. The latter either disrupt or preserve the reading frame
in most cases of Duchenne or Becker muscular dystrophy, respectively.
More than 99% of DMD patients display complete or almost
complete absence of dystrophin in skeletal muscle biopsy specimens. The
test is very specific because patients with neuromuscular diseases
other than DMD/BMD have normal dystrophin. Patients with
dystrophin levels between 5% and 20% of normal,
regardless of protein size, seem to develop an intermediate phenotype (mild
DMD or severe BMD). Patients with mild to moderate Becker phenotype
usually have levels above 20%.4
Before the age of 5 years, the serum creatine kinase levels are
usually 10 to 200 times the upper limit of normal, or even higher;
levels of 10,000 to 50,000 IU/L are not unusual in Duchenne
muscular dystrophy (DMD)/Becker muscular dystrophy (BMD).
In a child with DMD, during the first 3 years of life the serum
creatine kinase concentration is always more than 10 times the upper
limit of normal; if it is less than that, the diagnosis should be
The muscle biopsy results demonstrate degeneration, regeneration, isolated “opaque” hypertrophic
fibers, and significant replacement of muscle by fat and connective tissue.
In muscle biopsy tissue derived from DMD patients, there is complete
or almost complete absence of staining with antidystrophin antibodies,
but in BMD patients either normal or reduced patchy staining of
the sarcolemma is observed. In patients with other neuromuscular
diseases, there is homogeneous staining of the plasma membrane.1,5
Therapeutic interventions in DMD/BMD are aimed at maintaining
function, preventing contractures, and providing psychologic support.
Passive stretching exercises to prevent contractures of the iliotibial
band, the Achilles tendons, and flexors of the hip are the mainstays
of physical therapy. Lightweight plastic ankle-foot orthoses (AFOs)
should be applied if the foot remains in plantar flexion during
sleep. Standing and/or walking can be maintained by using
long leg braces. Surgery can be performed to release contractures
of the hip flexors, iliotibial bands, and Achilles tendons. Standing
and ambulation seem to prevent scoliosis. After the age of 10 years, pulmonary
function studies, electrocardiography, and echocardiography should
be performed annually or biannually to monitor the pulmonary and
cardiac functions. Overnight mouth intermittent positive pressure can
be used to treat symptomatic nocturnal hypoventilation, and respiratory
assistance may be used during periods of respiratory infection.
in Duchenne Muscular Dystrophy
Clinical studies have shown that prednisone improves the strength and
function of patients with DMD.6-8 Deflazacort is
a synthetic derivative of prednisolone used in Europe, but currently
unavailable in the United States. It has been suggested that deflazacort
has fewer side effects than prednisone, particularly relating to
The American Academy of Neurology and the Child Neurology Society
have published national practice parameters for the use of corticosteroid
therapy; some of the recommendations, which follow, are in accordance
with those parameters.11
- Offer boys with DMD, who are older than 5 years, treatment
with prednisone at a dose of 0.75 mg/kg/day. Discuss
carefully the potential benefits and risks of corticosteroid therapy
with the patient and family prior to initiating therapy.
- Assess the potential benefits of corticosteroid therapy.
- Continue the optimal maintenance dose of prednisone, 0.75
mg/kg/day, if side effects are not severe. Gradual
tapering of prednisone to as low as 0.3 mg/kg/day
supports significant but less robust improvement.
- DMD may also be treated using deflazacort 0.9 mg/kg/day.
Monitor side effects of weight gain and asymptomatic cataracts.
A number of strategies may be employed to prevent secondary complications
of DMD/BMD. Patients should be evaluated by pulmonary and
cardiac specialists prior to surgery and receive pneumococcal vaccine
and annual influenza vaccination.12 They should
receive exposure to sunshine as well as a balanced diet rich in
vitamin D and calcium to improve bone density and reduce the risk
of fractures. If the vitamin D serum concentration is less than 20
ng/mL, vitamin D supplementation may be initiated. Patients should
receive physical therapy to promote mobility and prevent contractures
and be encouraged to control weight and avoid obesity. Routine evaluation
by a nutritionist is recommended.
Individuals with DMD and BMD should receive routine monitoring
by a cardiologist for evidence of cardiomyopathy starting at around
the age of 10 years, and cardiac evaluation should be repeated annually
or biannually.2 Female carriers should be monitored
for dilated cardiomyopathy after their teenage years.13 DMD/BMD
patients should be monitored for orthopedic complications, especially
scoliosis, and receive surgical interventions as needed. Baseline
pulmonary function testing should be obtained before wheelchair
confinement, at about 9 to 10 years of age. A pediatric pulmonologist
should evaluate patients twice a year after any 1 of the following
events: wheelchair confinement, vital capacity reduced below 80% predicted,
or age 12 years.12
Experimental gene therapies are currently under investigation. PTC124,
a new, orally administered nonantibiotic drug, appears to promote
ribosomal read-through of nonsense (stop) mutations and has shown
encouraging results in preclinical efficacy studies in mdx mice.
A phase 1 multiple-dose safety trial of this potential therapy is
ongoing.14 Stem cell therapy is under investigation
but remains experimental. Myoblast transfer has been inefficient.
Creatine monohydrate has been studied as a potential treatment in
muscular dystrophies and neuromuscular disorders.15 Given
the limited data and modest benefit, treatment of Duchenne muscular
dystrophy with creatine monohydrate cannot be recommended.
Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive
(chromosome Xq28) or autosomal dominant or autosomal recessive condition
(chromosome 1q21) with onset in late childhood or adult life. Mutations
in the emerin (Xq28)16 and lamin A/C genes
(1q21)17 are responsible for the EDMD form of muscular
The muscle weakness and wasting in EDMD has a humeroperoneal
distribution, often starting in the arms, with weakness of both
the biceps and triceps and relative preservation of the deltoid
muscles.18 Later, distal leg weakness with atrophy
of the peroneal muscles is noted; mild facial weakness may be also
be observed. The myopathy tends to be slowly progressive. Contractures
at the elbows are noted early, often associated with toe-walking,
as the first manifestations of the disease. Contractures of the posterior
aspect of the neck, lower spine, and the Achilles tendons also occur.
Cardiac involvement is common and consists of cardiomyopathy, with
atrioventricular block and often atrial paralysis.19 The
cardiomyopathy may lead to sudden death in approximately 50% of
the affected individuals, usually early in adult life.
Laboratory studies show modest elevation of serum creatine kinase
levels, which are rarely above a few hundred units per liter. DNA
testing for emerin and lamin A/C gene mutations is now available.
A muscle biopsy can provide further evidence for the diagnosis of
X-linked EDMD by demonstrating absence of nuclear immunostaining
for emerin by immunohistochemistry.
Because the cardiac involvement in Emery-Dreifuss muscular dystrophy
is potentially fatal, the cardiac status of the patient should be investigated
even if he/she is asymptomatic. Installation of a cardiac
pacemaker may be lifesaving in patients with evidence of atrioventricular
block. Stretching exercises to prevent the development of contractures
should be the focus of physical therapy.
Myotonic dystrophy type 1 (DM1) is the most common form of muscular
dystrophy among those of European ancestry, with a prevalence of
3 to 5 per 100,000 population and an incidence of 1 in 8000. DM1
is a multisystem disorder, transmitted by autosomal dominant inheritance,
with variable penetrance. In the classical form, DM1 has its onset
in adolescence or adulthood, but a neonatal form also occurs. The
main clinical features of DM1 are myotonia (delayed muscle relaxation
after contraction), weakness and wasting affecting facial and distal
limb muscles, frontal balding (in males), cataracts, cardiomyopathy with
conduction defects, multiple endocrinopathies, hypersomnia, and
low intelligence or dementia. The face is long, with wasting of the
masseter and temporal muscles and variable ptosis and facial diplegia.
There may be associated dysarthria, hearing loss, swallowing difficulties,
and mild external ophthalmoplegia. Myotonia can be an early symptom,
demonstrated by percussion of muscles, usually of the thenar eminence,
and by difficulty with releasing the grasp or opening the eyes after
sustained closure. Later in the course of the disease, the progressive
muscle weakness and wasting become the predominant features, leading
to severe distal weakness in the hands and feet. Endocrinopathies include
hyperinsulinism, rarely diabetes, adrenal atrophy, hypothyroidism,
infertility in women, testicular atrophy, and growth hormone secretion
disturbances. Smooth and cardiac muscle involvement are usually
expressed by disturbed gastrointestinal mobility and cardiac conduction
Fifteen percent to 25% of offspring of affected DM1
mothers develop congenital myotonic dystrophy. The congenital form
of DM1 presents with profound hypotonia at birth, associated with facial
diplegia, feeding and respiratory difficulties, and skeletal deformities
such as clubfeet. Later, during childhood, delayed developmental
progression is noted in a pattern consistent with mental retardation.
Clinical myotonia is usually absent in neonates and infants. Brain
imaging reveals ventriculomegaly due to brain atrophy.
Although cardiac arrhythmia and atrioventricular block have been thought
to be rare in DM1, a retrospective study found that children with
the congenital or infantile form of DM1, and asymptomatic adolescents
with no or only subtle signs of myotonic dystrophy experienced serious
cardiac rhythm disturbances as early as the second decade of life.21 Thus
it has been recommended that the routine evaluation of young patients
with DM1 include exercise testing with EKG monitoring.
The identification of the myotonic dystrophy mutation has provided
a molecular blood test for almost 100% accurate diagnosis
of this disorder in both symptomatic and asymptomatic individuals.
The DM1 locus was mapped by linkage analysis to chromosome 19q13.3;
this genetic localization finally led to the recent identification
of the genetic defect in DM type 1, which is thought to be an amplified trinucleotide
CTG repeat, located in the 3′ untranslated
region of a gene that putatively encodes a serine-threonine protein
kinase (myotonin-protein kinase; DMK).22 Although
this CTG repeat is quite polymorphic, it is stable in normal individuals.
In contrast, the CTG repeat in DM1 chromosomes is unstable and can
become significantly large. In normal individuals, the 2 alleles
contain between 5 and 50 copies of the CTG repeat. However, normal
individuals with 38 to 49 copies of the repeat are classified in
a borderline or premutation category because of the small possibility
of expansion of the CTG repeat in their offspring or family members.
Mildly affected individuals or asymptomatic protomutation “carriers” have
50 to 80 CTG repeats, whereas symptomatic subjects have between
80 and 2000 or more copies (full mutation).
The pathogenesis of DM1 is probably multifactorial. Possible mechanisms
include a deficiency of the DMK protein, potential toxic effect
of intranuclear accumulation of abnormally expanded RNA transcripts,
an associated misregulation of RNA homeostasis, and a haploinsufficiency
of neighboring gene.23 In a study using skeletal
muscle from a transgenic mouse model of myotonic dystrophy, the
abnormal accumulation of abnormally expanded RNA molecules resulted
in defective splicing of the skeletal muscle chloride channel pre-mRNA.
The authors proposed that the loss of chloride channel protein from
the sarcolemma may lead to chloride channel dysfunction and membrane
hyperexcitability, resulting in myotonia.
The treatment of myotonic dystrophy is currently symptomatic.
As patients develop distal weakness, braces for foot drop are usually helpful.
The myotonia frequently responds to medications that stabilize membranes,
such as phenytoin, mexiletine, gabapentin, carbamazepine, and acetazolamide.
Neonates with congenital myotonic dystrophy type 1 (DM1) often require
continuous ventilatory support. Support required longer than 4 weeks
usually indicates a poor prognosis for survival. During the first
2 years of life, feeding difficulties are common; children with
congenital DM1 are at increased risk for aspiration and may benefit
from feeding evaluation. During the first 6 months of life, gastrostomy
tube insertion is often necessary to maintain nutrition and prevent
aspiration pneumonia. Clubfoot deformities require orthopedic care.
Myotonic Dystrophy Type
During the last 15 years, a subgroup of families with myotonia,
weakness, and cataracts, but with other features atypical for DM,
were identified because they had no abnormal expansion of the CTG
repeat in the DM gene on chromosome 19. Most patients are adults.
Myotonic dystrophy type 2 is also known as proximal myotonic myopathy
Limb-Girdle Muscular Dystrophies
The term limb-girdle dystrophy embraces a number
of conditions with heterogeneous etiologies; a European Neuromuscular
Center meeting in 1995 defined limb-girdle muscular dystrophy (LGMD) as
a muscular dystrophy with predominantly proximal distribution of
weakness that, early in the course of the disease, spares distal muscles
as well as facial and extraocular muscles.25 Most
cases are inherited in an autosomal recessive fashion and, as is
to be expected, are sporadic. However, families with an autosomal
dominant pattern of inheritance have also been described. The discovery
of the genetically distinct subtypes of LGMD has led to nomenclature
designating autosomal dominant LGMD as LGMD1A, 1B, 1C, and so forth, and
autosomal recessive LGMD as LGMD-2A, 2B, 2C, and so forth.26 The
current status of this classification is shown in Table
572-2. Mutations within the same gene may result in different
phenotypes, sometimes not consistent with the strict definition
of LGMD; for example, LGMD2B and Miyoshi distal myopathy are caused
by dysferlin gene mutations, whereas mutations in the gene encoding lamin
A/C may result in the phenotypes of autosomal dominant Emery-Dreifuss
muscular dystrophy, LGMD1B, or cardiomyopathy with conduction system disease.
Sarcoglycanopathies are early-onset autosomal recessive LGMDs caused
by mutations in α, β, γ,
and δ sarcoglycans, which are members of the dystrophin-associated
572-2. Limb-Girdle Muscular Dystrophies ||Download (.pdf)
572-2. Limb-Girdle Muscular Dystrophies
|LGMD1B||1q11-q21||Lamin A/C||Autosomal dominant|
|LGMD2H||9q31-q34.1||Tripartite motif containing protein 32||Autosomal recessive|
|LGMD2I||19q13.3||Fukutin-related protein||Autosomal recessive|
The age of onset of LGMD varies from early childhood to adulthood,
but typically the onset is not congenital. In some cases, weakness
may be noted early, leading to significant disability during childhood;
in others, the weakness may not be apparent until early in adult
life. The course is usually slowly progressive, but may be rapid
in a few cases. The weakness affect the shoulder girdle (scapulohumeral
type) or the pelvic girdle (pelvifemoral type) or both.
Serum creatine kinase levels are usually modestly elevated, but
can be very high in sarcoglycanopathies, dysferlinopathy, and caveolinopathy.
A muscle biopsy results reveal dystrophic changes. Prior to performing
a muscle biopsy, DNA testing for calpain 3, sarcoglycans (if available),
and fukutin-related protein (LGMD2I), as well as protein testing
for dysferlin in blood, are suggested.27 In
all patients with a Duchenne muscular dystrophy/Becker
muscular dystrophy phenotype and no detectable dystrophin gene mutations,
genetic testing for limb-girdle muscular dystrophy 2I is indicated.
If genetic and protein tests are uninformative or unavailable, the
next appropriate diagnostic procedure is a muscle biopsy. Immunohistochemistry
with antibodies against α, β, γ,
and δ sarcoglycans; dystrophin; dystroglycans;
and merosin may offer a means for a specific biopsy diagnosis (eg, α-sarcoglycanopathy),
but not always.
Treatment is supportive and is aimed at the prevention of contractures,
as substantial disability may result from them. Therefore, a passive
stretching physical therapy program is instituted early. Later in
the course of the disease, cardiorespiratory monitoring is indicated.
The classical form of facioscapulohumeral muscular dystrophy
(FSHD) is inherited in an autosomal dominant fashion and has been
mapped to chromosome 4q35. In this region, deletion of an integral
number of tandemly arrayed 3.3-kb repeat units (called D4Z4) has
a causal relationship to FSHD.28 The general population
exhibits a number of repeat units varying from 11 to more than 100;
patients with FSHD exhibit deletion of an integral number of these
units and an observed allele of 1 to 10 residual units.
It is hypothesized that D4Z4 contraction leads to the inappropriate overexpression
of 1 or more disease genes. Hypomethylation of D4Z4 may mediate
this effect. The overexpression of genes in the area may be responsible
for the phenotype, but that is not certain.29
Although FSHD is usually slowly progressive, it can be extremely
variable in its severity and even the age of onset. The infantile form
of FSHD has a very early onset (usually within the first few years
of life) and is rapidly progressive, usually with wheelchair confinement
by the age of 9 to 10 years. There is profound facial weakness,
inability to close the eyes in sleep, inability to smile and to show
any evidence of facial expression. The weakness rapidly involves
the shoulder and hip girdles, with lumbar lordosis, pronounced forward
pelvic tilt, and hyperextension of the knees and the head upon walking.
Marked weakness of the wrist extensors may result in a wrist drop.
The infantile variety of FSHD is often sporadic. Patients with infantile
FSHD and a small number of chromosome 4q35 repeats often have associated
mental retardation, epilepsy, and severe sensorineural hearing loss.
In the classical form of FSHD, the onset is usually in the second
or third decade, and the progression is slow, with almost normal
life span. The facial muscles are involved initially, with inability
to close the eyes tightly, smile, or whistle. The facial weakness, however,
can be mild early on and may remain mild for many years. The muscles
of the shoulders and upper arms are also involved with marked atrophy
of the biceps and triceps, but relative preservation of the deltoid
muscles. There is significant scapular winging. Exudative telangiectasia
of the retina (Coats syndrome) with an associated sensorineural
hearing loss occurs in both infantile and classical FSHD cases.
Cardiac involvement has been documented at various rates (4–60%)
in a published series regarding FSHD patients.
Serum creatine kinase levels are only mildly elevated, and rarely
elevated in patients presymptomatically. A blood DNA test is available
for FSHD; most patients with classic FSHD carry 1 to 10 residual
repeat units within the subtelomere of chromosome 4q (4q35). This
diagnostic test is positive in 95% to 98% of typical facioscapulohumeral
muscular dystrophy cases, but the sensitivity of the genetic test
for atypical cases remains uncertain. In typical cases, we see no
value in performing a muscle biopsy.
Treatment of facioscapulohumeral muscular dystrophy (FSHD) is
primarily supportive. There is need to examine the eyes for evidence of
exudative telangiectasia (Coats syndrome),30 which
is usually treatable with photocoagulation of the abnormal vessels
to prevent retinal detachment.
Infants with hypotonia and weakness at birth in whom muscle biopsies
show changes consistent with muscular dystrophy are described as
having congenital muscular dystrophy (CMD). Contractures of 2 or
more joints (arthrogryposis) are also commonly present in the newborn
Congenital muscular dystrophy includes a number of genetically
determined conditions in which muscular dystrophy is evident at birth.
Serum creatine kinase concentration is usually elevated. Abnormal
characteristics found as a result of muscle biopsy include extensive
fibrosis, degeneration and regeneration of muscle fibers, and proliferation
of fatty and connective tissue. In most patients, the clinical course
progresses very slowly, although in some cases it is static. Actual
improvement has been observed in a few cases.
The presence or absence of structural central nervous system
abnormalities, detected by neuroimaging or at autopsy, forms the
basis of CMD classification. Occidental, or classical, CMD, in which
such structural changes are absent, is thereby distinguished from
Fukuyama muscular dystrophy, Walker-Warburg syndrome, and muscle-eye-brain disease.
Classical CMD has been further classified based on identification
of mutations within the laminin α-2 chain gene
(merosin) into merosin-negative and merosin-positive subgroups.
The chromosomal location and respective genes identified for these
disorders appear in Table 572-3.
Table 572-3. Genetic
Loci for Congenital Muscular Dystrophy Identified to Date ||Download (.pdf)
Table 572-3. Genetic
Loci for Congenital Muscular Dystrophy Identified to Date
|Disease||Mode of Inheritance||Gene Location||Symbol (gene product)|
|Primary merosin deficiency (MDC1A)||Autosomal recessive||6q22-q23||LAMA2 (laminin α-2 chain of merosin)|
|Secondary merosin deficiency (MDC1B)||Autosomal recessive||1q42||?|
|Secondary merosin deficiency (MDC1C)||Autosomal recessive||19q13.3||FKRP (fukutin-related protein)|
|Rigid spine syndrome (RSMD)||Autosomal recessive||1p35-p36||RSMD1 (selenoprotein N)|
|Ullrich muscular dystrophy (UCMD)||Autosomal recessive||21q22.3||COL6A1 (collagen VI α-1 chain)|
|Ullrich muscular dystrophy (UCMD)||Autosomal recessive||21q22.3||COL6A2 (collagen VI α-2 chain)|
|Ullrich muscular dystrophy (UCMD)||Autosomal recessive||2q37||COL6A3 (collagen VI α-3 chain)|
|Integrin α-7 deficiency||Autosomal recessive||12q13||Integrin α -7|
Dystrophy with Central Nervous System Abnormalities|
|Fukuyama congenital muscular dystrophy||Autosomal recessive||9q31-q33||FCMD (fukutin)|
|Muscle-eye-brain disease||Autosomal recessive||1p32-p34||POMGnT1 (glycosyltransferase)|
|Muscle-eye-brain disease||Autosomal recessive||19q13.3||FKRP (fukutin-related protein)|
|Walker-Warburg syndrome||Autosomal recessive||9q34.1||POMT1 (O-mannosyltransferase)|
|Walker-Warburg syndrome||Autosomal recessive||9q31-q33||FCMD (fukutin)|
|Walker-Warburg syndrome||Autosomal recessive||19q13.3||FKRP (fukutin-related protein)|
|Walker-Warburg syndrome||Autosomal recessive||14q24.3||POMT2 (O-mannosyltransferase)|
|LARGE-related congenital muscular dystrophy (MDC1D)||Autosomal recessive||22q12.3||LARGE (putative glycosyltransferase)|
Clinical Presentation and
A severe classical form of CMD which is merosin-deficient, has
been described in children of European ancestry combined with high creatine
kinase levels and demyelination of the cerebral hemispheres without,
in most cases, structural central nervous system anomalies. The
associated mutated gene was mapped to chromosome 6q22-23 and identified
as encoding merosin, which is the -2 chain of laminin (LAM2) and
a component of the dystrophin-associated protein (DAP) complex (Fig. 572-2).31
Immunohistochemistry with antimerosin antibodies performed on
muscle biopsy specimens from these patients shows a diminished or
absent staining for the protein. Merosin-positive patients without
structural brain abnormalities usually have a milder phenotype and
are clinically and genetically heterogeneous.
Fukuyama CMD, one of the most common autosomal recessive disorders
in Japan (0.7 to 1.2 per 10,000 births), is characterized by hypotonia,
generalized weakness, severe developmental delay, seizures, microcephaly,
and elevated serum creatine kinase levels. EEG shows epileptiform
activity. Cerebral CT or MRI show cortical dysgenesis with pachygyria
and polymicrogyria in the temporal and occipital regions. Patients
may have simple myopia, but no structural changes to the eye.32
The genetic locus for Fukuyama CMD has been mapped to chromosome 9q31-33 and the mutated gene identified.
The respective protein, fukutin, is secreted outside the cell and
may be a component of the extracellular matrix reinforcing muscle
membranes. Pathologic studies of the brain have suggested that fukutin
is a constituent of the basement membrane.
CMD associated with ocular dysplasia, hydrocephalus, and cerebral
malformations is termed cerebro-ocular dysplasia or Walker-Warburg
syndrome.33 Ocular abnormalities include cataracts,
optic nerve hypoplasia, corneal clouding, and retinal dysplasia
or detachment. Serum creatine kinase concentration is mildly to
moderately elevated, and EMG shows myopathic changes. Brain MRI
shows a number of abnormalities: hypodense white matter, hypoplastic
cerebellum and pons, absent vermis and corpus callosum, fused hemispheres,
and ventricular dilatation with or without hydrocephalus; the pattern
of abnormal cortical development, known as type II lissencephaly
or cobblestone-type brain malformation, is present. Dandy-Walker cyst,
sometimes with posterior encephaloceles, is also associated with
this disorder. Patients with Walker-Warburg syndrome have a median
survival of only 4 months.
The gene for Walker-Warburg syndrome was mapped to chromosome
9q34.1, and a subset of Walker-Warburg syndrome patients were found
to have mutations in the O-mannosyltransferase
POMT1 gene.34 These mutations seem to result in defective
glycosylation of α-dystroglycan, which is a component
of the DAP complex (Fig. 572-2). Muscle biopsy
immunohistochemistry shows deficient α-dystroglycan
and partial staining for merosin.
A milder phenotype than Walker-Warburg syndrome, muscle-eye-brain
(MEB) disease is especially prevalent in Finland. Its typical presentation
is that of hypotonia, severe progressive myopia from infancy, and
developmental delay.35 With advancing age, patients develop
pale retina, low or flat electroretinogram, and visual failure related
to retinal degeneration. Patients commonly experience seizures and
often display severe cognitive impairment. Most patients experience
a decline in motor function around age 5 years, at which time they
develop contractures and spasticity.
Serum creatine phosphokinase levels are elevated in MEB disease.
Brain MRI in MEB disease shows cobblestone lissencephaly less severe
than that seen in Walker-Warburg syndrome and also shows a characteristically
flat brain stem. Immunohistochemistry on muscle biopsy in MEB disease
shows normal dystrophin as well as other dystrophin-associated proteins,
with the exceptions of deficient α-dystroglycan
and diminished but present merosin.
The genetic locus for MEB disease has been mapped to chromosome
1p32-p34 and the disease results from mutations of the POMGNT1 gene.
In MEB disease as well as in other congenital muscular dystrophies,
selective deficiency and hypoglycosylation of -dystroglycan may
play an etiologic role.
Congenital muscular dystrophy (CMD) presents in the newborn period
as a floppy baby, often with arthrogryposis. Serum creatine kinase
levels are variably elevated in CMD. At this time, commercial DNA
tests are not readily available for merosin, collagen VI, fukutin, POMT1,
or POMGnT1 mutations; therefore, diagnosis is based
on findings of widespread dystrophic changes in muscle biopsy specimens
and on muscle immunohistochemical examination with anti-merosin,
anti-collagen VI, and anti-α-dystroglycan antibodies,
which usually reveal an absence of the respective protein in the
sarcolemma of the muscle fibers. Brain or ocular abnormalities should
be excluded by MRI and eye examination.
No definitive treatment is available for these disorders.