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Gale Encyclopedia of Medicine ..

Gale Encyclopedia of Medicine


Muscular dystrophy

Author/s: Richard Robinson

Definition
Muscular dystrophy is the name for a group of inherited
disorders in which strength and muscle bulk gradually
decline. Nine types of muscular dystrophies are generally
recognized.

Description
The muscular dystrophies include:

Duchenne muscular dystrophy (DMD): DMD affects young boys,
causing progressive muscle weakness, usually beginning in
the legs. It is the most severe form of muscular dystrophy.
DMD occurs in about 1 in 3,500 male births, and affects
approximately 8,000 boys and young men in the United
States. A milder form occurs in very few female carriers.
Becker muscular dystrophy (BMD): BMD affects older boys and
young men, following a milder course than DMD. BMD occurs
in about 1 in 30,000 male births.
Emery-Dreifuss muscular dystrophy (EDMD): EDMD affects
young boys, causing contractures and weakness in the
calves, weakness in the shoulders and upper arms, and
problems in the way electrical impulses travel through the
heart to make it beat (heart conduction defects). Fewer
than 300 cases of EDMD have been identified.
Limb-girdle muscular dystrophy (LGMD): LGMD begins in late
childhood to early adulthood and affects both men and
women, causing weakness in the muscles around the hips and
shoulders. It is the most variable of the muscular
dystrophies, and there are several different forms of the
disease now recognized. Many people with suspected LGMD
have probably been misdiagnosed in the past, and therefore
the prevalence of the disease is difficult to estimate. The
number of people affected in the United States may be in
the low thousands.
Facioscapulohumeral muscular dystrophy (FSH): FSH, also
known as Landouzy-Dejerine disease, begins in late
childhood to early adulthood and affects both men and
women, causing weakness in the muscles of the face,
shoulders, and upper arms. The hips and legs may also be
affected. FSH occurs in about 1 out of every 20,000 people,
and affects approximately 13,000 people in the United
States.
Myotonic dystrophy: also known as Steinert's disease,
affects both men and women, causing generalized weakness
first seen in the face, feet, and hands. It is accompanied
by the inability to relax the affected muscles (myotonia).
Symptoms may begin from birth through adulthood. It is the
most common form of muscular dystrophy, affecting more than
30,000 people in the United States.
Oculopharyngeal muscular dystrophy (OPMD): OPMD affects
adults of both sexes, causing weakness in the eye muscles
and throat. It is most common among French Canadian
families in Quebec, and in Spanish-American families in the
southwestern United States.
Distal muscular dystrophy (DD): DD begins in middle age or
later, causing weakness in the muscles of the feet and
hands. It is most common in Sweden, and rare in other parts
of the world.
Congenital muscular dystrophy (CMD): CMD is present from
birth, results in generalized weakness, and usually
progresses slowly. A subtype, called Fukuyama CMD, also
involves mental retardation. Both are rare; Fukuyama CMD is
more common in Japan.


Causes & symptoms
Causes
Several of the muscular dystrophies, including DMD, BMD,
CMD, and most forms of LGMD, are due to defects in the
genes for a complex of muscle proteins. This complex spans
the muscle cell membrane to unite a fibrous network on the
interior of the cell with a fibrous network on the outside.
Current theory holds that by linking these two networks,
the complex acts as a "shock absorber," redistributing and
evening out the forces generated by contraction of the
muscle, thereby preventing rupture of the muscle membrane.
Defects in the proteins of the complex lead to
deterioration of the muscle. Symptoms of these diseases set
in as the muscle gradually exhausts its ability to repair
itself. Both DMD and BMD are caused by flaws in the gene
for the protein called dystrophin. The flaw leading to DMD
prevents the formation of any dystrophin, while that of BMD
allows some protein to be made, accounting for the
differences in severity and onset between the two diseases.
Differences among the other diseases in the muscles
involved and the ages of onset are less easily explained.

The causes of the other muscular dystrophies are not as
well understood:

One form of LGMD is caused by defects in the gene for a
muscle enzyme, calpain. The relationship between this
defect and the symptoms of the disease is unclear.
EDMD is due to a defect in the gene for a protein called
emerin, which is found in the membrane of a cell's nucleus,
but whose exact function is unknown.
Myotonic dystrophy is linked to gene defects for a protein
that may control the flow of charged particles within
muscle cells. This gene defect is called a triple repeat,
meaning it contains extra triplets of DNA code. It is
possible that this mutation affects nearby genes as well,
and that the widespread symptoms of myotonic dystrophy are
due to a range of genetic disruptions.
The gene for OPMD appears to also be mutated with a triple
repeat. The function of the affected protein may involve
translation of genetic messages in a cell's nucleus.
The cause of FSH is unknown. Although the genetic region
responsible for it has been localized on its chromosome,
the identity and function of the gene or genes involved had
not been determined as of 1997.
The gene responsible for DD has not yet been found.
Genetics and patterns of inheritance
The muscular dystrophies are genetic diseases, meaning they
are caused by defects in genes. Genes, which are linked
together on chromosomes, have two functions: They code for
the production of proteins, and they are the material of
inheritance. Parents pass along genes to their children,
providing them with a complete set of instructions for
making their own proteins.

Because both parents contribute genetic material to their
offspring, each child carries two copies of almost every
gene, one from each parent. For some diseases to occur,
both copies must be flawed. Such diseases are called
autosomal recessive diseases. Some forms of LGMD and DD
exhibit this pattern of inheritance, as does CMD. A person
with only one flawed copy, called a carrier, will not have
the disease, but may pass the flawed gene on to his
children. When two carriers have children, the chances of
having a child with the disease is one in four for each
pregnancy.


Other diseases occur when only one flawed gene copy is
present. Such diseases are called autosomal dominant
diseases. Other forms of LGMD exhibit this pattern of
inheritance, as do DM, FSH, OPMD, and some forms of DD.
When a person affected by the disease has a child with
someone not affected, the chances of having an affected
child is one in two.

Because of chromosomal differences between the sexes, some
genes are not present in two copies. The chromosomes that
determine whether a person is male or female are called the
X and Y chromosomes. A person with two X chromosomes is
female, while a person with one X and one Y is male. While
the X chromosome carries many genes, the Y chromosome
carries almost none. Therefore, a male has only one copy of
each gene on the X chromosome, and if it is flawed, he will
have the disease that defect causes. Such diseases are said
to be X-linked. X-linked diseases include DMD, BMD, and
EDMD. Women aren't usually affected by X-linked diseases,
since they will likely have one unaffected copy between the
two chromosomes. Some female carriers of DMD suffer a mild
form of the disease, probably because their one unaffected
gene copy is shut down in some of their cells.

Women carriers of X-linked diseases have a one in two
chance of passing the flawed gene on to each child born.
Daughters who inherit the disease gene will be carriers. A
son born without the disease gene will be free of the
disease and cannot pass it on to his children. A son born
with the defect will have the disease. He will pass the
flawed gene on to each of his daughters, who will then be
carriers, but to none of his sons (because they inherit his
Y chromosome).

Not all genetic flaws are inherited. As many as one third
of the cases of DMD are due to new mutations that arise
during egg formation in the mother. New mutations are less
common in other forms of muscular dystrophy.

Symptoms
All of the muscular dystrophies are marked by muscle
weakness as the major symptom. The distribution of
symptoms, age of onset, and progression differ
significantly. Pain is sometimes a symptom of each, usually
due to the effects of weakness on joint position.

DMD
A boy with Duchenne muscular dystrophy usually begins to
show symptoms as a pre-schooler. The legs are affected
first, making walking difficult and causing balance
problems. Most patients walk three to six months later than
expected and have difficulty running. Later on, the boy
with DMD will push his hands against his knees to rise to a
standing position, to compensate for leg weakness. About
the same time, his calves will begin to swell, though with
fibrous tissue rather than with muscle, and feel firm and
rubbery; this condition gives DMD one of its alternate
names, pseudohypertrophic muscular dystrophy. He will widen
his stance to maintain balance, and walk with a waddling
gait to advance his weakened legs. Contractures (permanent
muscle tightening) usually begin by age five or six, most
severely in the calf muscles. This pulls the foot down and
back, forcing the boy to walk on tip-toes, called equinus,
and further decreases balance. Frequent falls and broken
bones are common beginning at this age. Climbing stairs and
rising unaided may become impossible by age nine or ten,
and most boys use a wheelchair for mobility by the age of
12. Weakening of the trunk muscles around this age often
leads to scoliosis (a side-to-side spine curvature) and
kyphosis (a front-to-back curvature).


The most serious weakness of DMD is weakness of the
diaphragm, the sheet of muscles at the top of the abdomen
that perform the main work of breathing and coughing.
Diaphragm weakness leads to reduced energy and stamina, and
increased lung infection because of the inability to cough
effectively. Young men with DMD often live into their
twenties and beyond, provided they have mechanical
ventilation assistance and good respiratory hygiene.

About one third of boys with DMD experience specific
learning disabilities, including trouble learning by ear
rather than by sight and trouble paying attention to long
lists of instructions. Individualized educational programs
usually compensate well for these disabilities.

BMD
The symptoms of BMD usually appear in late childhood to
early adulthood. Though the progression of symptoms may
parallel that of DMD, the symptoms are usually milder and
the course more variable. The same pattern of leg weakness,
unsteadiness, and contractures occur later for the young
man with BMD, often allowing independent walking into the
twenties or early thirties. Scoliosis may occur, but is
usually milder and progresses more slowly. Heart muscle
disease (cardiomyopathy), occurs more commonly in BMD.
Problems may include irregular heartbeats (arrhythmias) and
congestive heart failure. Symptoms may include fatigue,
shortness of breath, chest pain, and dizziness. Respiratory
weakness also occurs, and may lead to the need for
mechanical ventilation.

EDMD
This type of muscular dystrophy usually begins in early
childhood, often with contractures preceding muscle
weakness. Weakness affects the shoulder and upper arm
originally, along with the calf muscles, leading to foot-
drop. Most men with EDMD survive into middle age, although
a defect in the heart's rhythm (heart block) may be fatal
if not treated with a pacemaker.

LGMD
While there are at least a half-dozen genes that cause the
various types of LGMD, two major clinical forms of LGMD are
usually recognized. A severe childhood form is similar in
appearance to DMD, but is inherited as an autosomal
recessive trait. Symptoms of adult-onset LGMD usually
appear in a person's teens or twenties, and are marked by
progressive weakness and wasting of the muscles closest to
the trunk. Contractures may occur, and the ability to walk
is usually lost about 20 years after onset. Some people
with LGMD develop respiratory weakness that requires use of
a ventilator. Lifespan may be somewhat shortened.
(Autosomal dominant forms usually occur later in life and
progress relatively slowly.)

FSH
FSH varies in its severity and age of onset, even among
members of the same family. Symptoms most commonly begin in
the teens or early twenties, though infant or childhood
onset is possible. Symptoms tend to be more severe in those
with earlier onset. The disease is named for the regions of
the body most severely affected by the disease: muscles of
the face (facio-), shoulders (scapulo-), and upper arms
(humeral). Hips and legs may be affected as well. Children
with FSH often develop partial or complete deafness.


The first symptom noticed is often difficulty lifting
objects above the shoulders. The weakness may be greater on
one side than the other. Shoulder weakness also causes the
shoulder blades to jut backward, called scapular winging.
Muscles in the upper arm often lose bulk sooner than those
of the forearm, giving a "Popeye" appearance to the arms.
Facial weakness may lead to loss of facial expression,
difficulty closing the eyes completely, and inability to
drink through a straw, blow up a balloon, or whistle. A
person with FSH may not develop strong facial wrinkles.
Contracture of the calf muscles may cause foot-drop,
leading to frequent tripping over curbs or rough spots.
People with earlier onset often require a wheelchair for
mobility, while those with later onset rarely do.

Myotonic dystrophy
Symptoms of Myotonic dystrophy include facial weakness and
a slack jaw, drooping eyelids (ptosis), and muscle wasting
in the forearms and calves. A person with this dystrophy
has difficulty relaxing his grasp, especially if the object
is cold. Myotonic dystrophy affects heart muscle, causing
arrhythmias and heart block, and the muscles of the
digestive system, leading to motility disorders and
constipation. Other body systems are affected as well:
Myotonic dystrophy may cause cataracts, retinal
degeneration, low IQ, frontal balding, skin disorders,
testicular atrophy, sleep apnea, and insulin resistance. An
increased need or desire for sleep is common, as is
diminished motivation. Severe disability affects most
people with this type of dystrophy within 20 years of
onset, although most do not require a wheelchair even late
in life.

OPMD
OPMD usually begins in a person's thirties or forties, with
weakness in the muscles controlling the eyes and throat.
Symptoms include drooping eyelids, difficulty swallowing
(dysphagia), and weakness progresses to other muscles of
the face, neck, and occasionally the upper limbs.
Swallowing difficulty may cause aspiration, or the
introduction of food or saliva into the airways. Pneumonia
may follow.

DD
DD usually begins in the twenties or thirties, with
weakness in the hands, forearms, and lower legs. Difficulty
with fine movements such as typing or fastening buttons may
be the first symptoms. Symptoms progress slowly, and the
disease usually does not affect life span.

CMD
CMD is marked by severe muscle weakness from birth, with
infants displaying "floppiness" and very little voluntary
movement. Nonetheless, a child with CMD may learn to walk,
either with or without some assistive device, and live into
young adulthood or beyond. In contrast, children with
Fukuyama CMD are rarely able to walk, and have severe
mental retardation. Most children with this type of CMD die
in childhood.

Diagnosis
Diagnosis of muscular dystrophy involves a careful medical
history and a thorough physical exam to determine the
distribution of symptoms and to rule out other causes.
Family history may give important clues, since all the
muscular dystrophies are genetic conditions (though no
family history will be evident in the event of new
mutations).


Labtestsmayinclude:

Blood level of the muscle enzyme creatine kinase (CK). CK
levels rise in the blood due to muscle damage, and may be
seen in some conditions even before symptoms appear.
Muscle biopsy, in which a small piece of muscle tissue is
removed for microscopic examination. Changes in the
structure of muscle cells and presence of fibrous tissue or
other aberrant structures are characteristic of different
forms of muscular dystrophy. The muscle tissue can also be
stained to detect the presence or absence of particular
proteins, including dystrophin.
Electromyogram (EMG). This electrical test is used to
examine the response of the muscles to stimulation.
Decreased response is seen in muscular dystrophy. Other
characteristic changes are seen in DM.
Genetic tests. Several of the muscular dystrophies can be
positively identified by testing for the presence of the
mutated gene involved. Accurate genetic tests are available
for DMD, BMD, DM, several forms of LGMD, and EDMD.
Other specific tests as necessary. For EDMD and BMD, for
example, an electrocardiogram may be needed to test heart
function, and hearing tests are performed for children with
FSH.
For most forms of muscular dystrophy, accurate diagnosis is
not difficult when done by someone familiar with the range
of diseases. There are exceptions, however. Even with a
muscle biopsy, it may be difficult to distinguish between
FSH and another muscle disease, polymyositis. Childhood-
onset LGMD is often mistaken for the much more common DMD,
especially when it occurs in boys. BMD with an early onset
appears very similar to DMD, and a genetic test may be
needed to accurately distinguish them. The muscular
dystrophies may be confused with diseases involving the
motor neurons, such as spinal muscular atrophy; diseases of
the neuromuscular junction, such as myasthenia gravis; and
other muscle diseases, as all involve generalized weakening
of varying distribution.

Treatment
Drugs
There are no cures for any of the muscular dystrophies.
Prednisone, a corticosteroid, has been shown to delay the
progression of DMD somewhat, for reasons that are still
unclear. Prednisone is also prescribed for BMD, though no
controlled studies have tested its benefit. A related drug,
deflazacort, appears to have similar benefits with fewer
side effects. It is available and is prescribed in Canada
and Mexico, but is unavailable in the United States.
Albuterol, an adrenergic agonist, has shown some promise
for FSH in small trials; larger trials are scheduled for
1998. No other drugs are currently known to have an effect
on the course of any other muscular dystrophy.

Treatment of muscular dystrophy is mainly directed at
preventing the complications of weakness, including
decreased mobility and dexterity, contractures, scoliosis,
heart defects, and respiratory insufficiency.

Physical therapy
Physical therapy, in particular regular stretching, is used
to maintain the range of motion of affected muscles and to
prevent or delay contractures. Braces are used as well,
especially on the ankles and feet to prevent equinus. Full-
leg braces may be used in DMD to prolong the period of
independent walking. Strengthening other muscle groups to
compensate for weakness may be possible if the affected
muscles are few and isolated, as in the earlier stages of
the milder muscular dystrophies. Regular, nonstrenuous
exercise helps maintain general good health. Strenuous
exercise is usually not recommended, since it may damage
muscles further.


Surgery
When contractures become more pronounced, tenotomy surgery
may be performed. In this operation, the tendon of the
contractured muscle is cut, and the limb is braced in its
normal resting position while the tendon regrows. In FSH,
surgical fixation of the scapula can help compensate for
shoulder weakness. For a person with OPMD, surgical lifting
of the eyelids may help compensate for weakened muscular
control. For a person with DM, sleep apnea may be treated
surgically to maintain an open airway. Scoliosis surgery is
often needed in DMD, but much less often in other muscular
dystrophies. Surgery is recommended at a much lower degree
of curvature for DMD than for scoliosis due to other
conditions, since the decline in respiratory function in
DMD makes surgery at a later time dangerous. In this
surgery, the vertebrae are fused together to maintain the
spine in the upright position. Steel rods are inserted at
the time of operation to keep the spine rigid while the
bones grow together.

When any type of surgery is performed in patients with
muscular dystrophy, anesthesia must be carefully selected.
People with MD are susceptible to a severe reaction, known
as malignant hyperthermia, when given halothane anesthetic.

Occupational therapy
The occupational therapist suggests techniques and tools to
compensate for the loss of strength and dexterity.
Strategies may include modifications in the home, adaptive
utensils and dressing aids, compensatory movements and
positioning, wheelchair accessories, or communication aids.

Nutrition
Good nutrition helps to promote general health in all the
muscular dystrophies. No special diet or supplement has
been shown to be of use in any of the conditions. The
weakness in the throat muscles seen especially in OPMD and
later DMD may necessitate the use of a gastrostomy tube,
inserted in the stomach to provide nutrition directly.

Cardiac care
The arrhythmias of EDMD and BMD may be treatable with
antiarrhythmia drugs such as mexiletine or nifedipine. A
pacemaker may be implanted if these do not provide adequate
control. Heart transplants are increasingly common for men
with BMD.

Respiratory care
People who develop weakness of the diaphragm or other
ventilatory muscles may require a mechanical ventilator to
continue breathing deeply enough. Air may be administered
through a nasal mask or mouthpiece, or through a
tracheostomy tube, which is inserted through a surgical
incision through the neck and into the windpipe. Most
people with muscular dystrophy do not need a tracheostomy,
although some may prefer it to continual use of a mask or
mouthpiece. Supplemental oxygen is not needed. Good hygiene
of the lungs is critical for health and longterm survival
of a person with weakened ventilatory muscles. Assisted
cough techniques provide the strength needed to clear the
airways of secretions; an assisted cough machine is also
available and provides excellent results.


Experimental treatments
Two experimental procedures aiming to cure DMD have
attracted a great deal of attention in the past decade. In
myoblast transfer, millions of immature muscle cells are
injected into an affected muscle. The goal of the treatment
is to promote the growth of the injected cells, replacing
the defective host cells with healthy new ones. Despite
continued claims to the contrary by a very few researchers,
this procedure is widely judged a failure. Modifications in
the technique may change that in the future.

Gene therapy introduces good copies of the dystrophin gene
into muscle cells. The goal is to allow the existing muscle
cells to use the new gene to produce the dystrophin it
cannot make with its flawed gene. Problems have included
immune rejection of the virus used to introduce the gene,
loss of gene function after several weeks, and an inability
to get the gene to enough cells to make a functional
difference in the affected muscle. Nonetheless, after a
number of years of refining the techniques in mice,
researchers are beginning human trials in 1998.

Prognosis
The expected lifespan for a male with DMD has increased
significantly in the past two decades. Most young men will
live into their early or mid-twenties. Respiratory
infections become an increasing problem as their breathing
becomes weaker, and these infections are usually the cause
of death.

The course of the other muscular dystrophies is more
variable; expected life spans and degrees of disability are
hard to predict, but may be related to age of onset and
initial symptoms. Prediction is made more difficult
because, as new genes are discovered, it is becoming clear
that several of the dystrophies are not uniform disorders,
but rather symptom groups caused by different genes.

People with dystrophies with significant heart involvement
(BMD, EDMD, Myotonic dystrophy) may nonetheless have almost
normal life spans, provided that cardiac complications are
monitored and treated aggressively. The respiratory
involvement of BMD and LGMD similarly require careful and
prompt treatment.

Prevention
There is no way to prevent any of the muscular dystrophies
in a person who has the genes responsible for these
disorders. Accurate genetic tests, including prenatal
tests, are available for some of the muscular dystrophies.
Results of these tests may be useful for purposes of family
planning.

Key Terms
Autosomal dominant
Diseases that occur when a person inherits only one flawed
copy of the gene.
Autosomal recessive
Diseases that occur when a person inherits two flawed
copies of a gene--one from each parent.
Becker muscular dystrophy (BMD)
A type of muscular dystrophy that affects older boys and
men, and usually follows a milder course than DMD.
Contractures
A permanent shortening (as of muscle, tendon, or scar
tissue) producing deformity or distortion.
Distal muscular dystrophy (DD)
A form of muscular dystrophy that usually begins in middle
age or later, causing weakness in the muscles of the feet
and hands.


Duchenne muscular dystrophy (DMD)
The most severe form of muscular dystrophy, DMD usually
affects young boys and causes progressive muscle weakness,
usually beginning in the legs.
Dystrophin
A protein that helps muscle tissue repair itself. Both DMD
and BMD are caused by flaws in the gene that instructs the
body how to make this protein.
Facioscapulohumeral muscular dystrophy (FSH)
This form of muscular dystrophy, also known as Landouzy-
Dejerine disease, begins in late childhood to early
adulthood and affects both men and women, causing weakness
in the muscles of the face, shoulders, and upper arms.
Limb-girdle muscular dystrophy (LGMD)
This form of muscular dystrophy begins in late childhood to
early adulthood and affects both men and women, causing
weakness in the muscles around the hips and shoulders.
Myotonic dystrophy
This type of muscular dystrophy, also known as Steinert's
disease, affects both men and women, causing generalized
weakness first seen in the face, feet, and hands. It is
accompanied by the inability to relax the affected muscles
(myotonia).
Oculopharyngeal muscular dystrophy (OPMD)
This type of muscular dystrophy affects adults of both
sexes, causing weakness in the eye muscles and throat.
Further Reading
For Your Information
Books
Brooke, Michael H. A Clinician's View of Neuromuscular
Diseases, 2nd ed. Williams & Wilkins, 1986.
Emery, Alan. Muscular Dystrophy: The Facts. Oxford Medical
Publications, 1994.
Swash, Michael, and Martin Schwartz. Neuromuscular
Diseases: A Practical Approach to Diagnosis and Management,
3rd edition. Springer, 1997.
Organizations
Muscular Dystrophy Association. 3300 East Sunrise Drive,
Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717.
http://www.mdausa.org.

Gale Encyclopedia of Medicine. Gale Research, 1999.


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