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Clinical
Picture
The muscles most affected in
LGMD (shown to the right in red) are those surrounding
the shoulders and hips. The nearby muscles in the thighs
and upper arms sometimes also weaken over the years.
Typically, there is onset of muscle weakness in the pelvic
area, called the pelvic girdle. This typically begins
in childhood or early adulthood. The first symptoms in
LGMD may be difficulty standing from a sitting position
without using arms and when climbing stairs. The individual
may also have a waddling gate. Later there is onset of
shoulder weakness, as shown by difficulty with tasks that
involve raising their arms, such as reaching and carrying.
In general, after the onset of arm weakening, the individual
with LGMD retains the ability to walk for 20 - 30 years.
Usually the muscle deterioration associated with LGMD
is not painful, but the limited mobility may lead to muscle
soreness and joint pain. This can be treated with exercises,
warm baths, and medications if necessary. Individuals
with a form of LGMD can lead happy, productive lives.
The brain, intellect and the senses are not affected in
individuals with LGMD. People with this type of muscular
dystrophy can think, see, hear and feel normally. People
with one of these disorders maintain control over their
bowel and bladder functions and have normal sexual function.
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Figure 1.
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Other Ways LGMD Can Affect the Body
In more rare and severe instances, some people with longstanding
LGMD may develop cardiomyopathy (weakening of the heart muscle),
conduction abnormalities (arrhythmias), or weakening of the
respiratory muscles. This can put the individual at risk for
heart failure. The major symptoms to watch for as indications
of heart or breathing involvement are palpitations, fainting
spells, shorteness of breath or foot swelling. The effects of
cardiomyopathy can be reduced and treated.
Different people have different levels of symptoms of LGMD.
Some people have only mild skeletal muscle problems, while others
have more severe muscle deterioration and severe cardiac complications.
It is important that patients with LGMD have their heart checked
regularly. The majority of the muscles affected in LGMD are
the voluntary muscles. However, some forms of LGMD may affect
the involuntary muscles that regulate normal blood vessel contraction
and relaxation. This potential involvement could be a factor
in some of the heart problems that occasionally are seen in
patients with LGMD.
It is not yet possible to predict the course that LGMD will
take in an individual. But we do know that LGMD is not a fatal
disease. Most of the danger comes from weakening of the heart
or respiratory muscles. Awareness of these problems and the
treatment that is available for them can lead to a longer and
higher quality life.
What Causes LGMD
Researchers have now identified at least 15 different forms
of LGMD. The types are usually classified by the genetic alterations
that cause them. Most of the LGMD gene defects lead to the failure
of production of key muscle proteins.
Many of the genes that cause LGMD produce proteins that are
normally located in the muscle cell membrane. The cell membrane,
also called the sarcolemma, is a protective, thin covering surrounding
each muscle fiber. Human skeletal muscles are made up of special
cells (myofibers) that are surrounded by the sarcolemma and
are arranged in bundles. Several proteins surround each muscle
fiber along the membrane and are essential for our muscle cells
to function normally. These proteins work together, and when
one of them is absent or malfunctioning, often the result is
muscular dystrophy. For instance, in the case of LGMD, a missing
membrane protein may result in a muscle cell membrane that lacks
its normal shock absorber abilities and that may leak substances
that it is not supposed to. For a more thorough review of muscle
anatomy, please refer to our Muscle
Anatomy Review section.
Some of the proteins associated with LGMD are not in the cell
membrane, but are located inside the muscle cell. There are
still some causes of different forms of LGMD that we do not
understand, as well as some forms of LGMD that have yet to be
discovered or classified. Further research is necessary to learn
more about this group of muscle diseases so that we can better
diagnose and treat the different types of LGMD.
Below is a list of the different forms of LGMD that have been
classified, the inheritance pattern they follow, the gene product
that is affected, and the genetic location responsible for that
form of LGMD.
| Inheritance |
Disorder |
Gene Product |
Chromosome Location |
| Autosomal Dominant |
LGMD1A
LGMD1B
LGMD1C
LGMD1D
LGMD1E
LGMD1F
|
Myotilin
Lamin A/C
Caveolin-3
?
?
? |
5q
1q
3p
6q
5q
7q |
| Autosomal Recessive |
LGMD2A
LGMD2B
LGMD2C
LGMD2D
LGMD2E
LGMD2F
LGMD2G
LGMD2H
LGMD2I |
Calpain-3
Dysferlin
Gamma-sarcoglycan
Alpha-sarcoglycan
Beta-sarcoglycan
Delta-sarcoglycan
Telethonin
TRIM32
FKRP |
15q
2p
13q
17q
4q
5q
17q
9q
19q |
All these mutations occur on one of the so-called autosomes.
These are the non-sex chromosomes (chromosomes 1 through 22)
that both males and females have in common. This means that,
unlike Duchenne and Becker Muscular Dystrophy, both males
and females are equally likely to inherit a genetic alteration
that leads to LGMD. As can be see in the above chart, most
forms of LGMD are autosomal recessive. This means that a person
needs to inherit an altered gene from both his mother and
his father to get LGMD. Therefore if a mother and a father
carry a genetic alteration in a LGMD gene, there is a 25%
risk with each pregnancy that the baby will inherit both copies
of the altered gene and thus be affected with LGMD. There
are also six types of LGMD that show autosomal dominant inheritance.
This type of inheritance is characterized by the need to inherit
only one copy of an altered gene (from either the mother or
the father) in order to get LGMD. Therefore, if one parent
carries a genetic alteration for a form of LGMD, there is
a 50% risk with each pregnancy that this alteration will be
passed on to the child, who will then develop LGMD. Please
visit our Genetics Review
section for a review of important genetic concepts.
Ways a person gets LGMD:
There are two main ways that an individual can get a form of
LGMD.
- Inheritance of the genetic alteration from the parents.
In this instance, a mother and/or a father pass on an altered
LGMD-causing gene to their son or daughter. There are two
types of inheritance patterns by which this can happen.
Autosomal recessive forms: Both a mother and a father
may pass on an altered gene to their son or daughter. The
parents are healthy carriers, but the child who inherits
two mutated copies of the given LGMD gene is affected. A
son or a daughter who inherits only one altered gene carries
the defect but does not show the disease. A parent affected
with LGMD will pass one of the two altered genes
on to every child. However, that child will not develop
LGMD unless the child also inherits a genetic mutation in
the same gene from a second parent. This is an unlikely
event.
Autosomal dominant forms: An affected parent who
has an altered gene can pass on this altered gene to a child.
There is a 50% chance (or a 1 in 2 chance) with every pregnancy
that an affected parent will pass on the altered gene to
the child.
- Development of a new mutation that is not inherited from
a parent. A new gene defect is called a sporadic mutation.
In autosomal recessive forms of LGMD, in addition to inheriting
an altered LGMD gene from a parent, an individual can develop
a new mutation in the second copy of the gene. This typically
occurs in the sperm or egg that formed the embryo from which
the individual developed. In autosomal dominant forms of
LGMD, a single new alteration in one of the LGMD genes is
enough to cause disease. If this occurs, then the only family
members at risk for LGMD other than the affected person
are that person’s children.
It may be that a person is the first in the family to have
LGMD. This can happen if there is a new sporadic mutation
that is dominant. It also can happen if there is an autosomal
recessive form of LGMD in the family. When a person is the
first in the family to have an autosomal recessive form of
the disorder, this usually reflects the fact that this is
the only family member to inherit two copies of the altered
LGMD gene (one from each parent). Unaffected siblings may
be carriers of only one defective gene, in which case they
will not have symptoms. It is not unusual for carriers of
a rare autosomal recessive disease not to know they are carriers
until some one in the family develops the rare genetic disease.
Other family members may be carriers, having no disease symptoms.
Carriers have the genetic alteration on a chromosome and can
have a child with the disease, but only if the child’s
other parent is also a carrier.
Because of the numerous forms of LGMD, inheritance risks for
any particular form may be complicated and depend on several
circumstances. It is best to find out more from your Muscular
Dystrophy Association clinic physician, a qualified neuromuscular
physician, or a genetic counselor.
Testing for and Diagnosing LGMD
The first step in diagnosing muscular dystrophy is noticing
the signs of muscular weakness in your child or in the affected
individual. Next, a visit with a physician will include a detailed
physical examination and detailed questions, including asking
about the patient and the family medical histories. The doctor
or nurse may ask many questions about the patient’s siblings,
parents, aunts and uncles, grandparents and cousins and construct
a family tree, which is called a pedigree. A physical examination
will focus on muscle weakness and the nervous system. Additional
studies such as electrical tests of nerve and muscle (electromyogram
or EMG) may be performed. Together, these studies determine
whether the patient’s weakness is a result of problems
with muscles, nerves, spinal cord or brain.
Sometimes doctors will order a special blood test that measures
an enzyme in one's blood called creatine kinase, or CK. When
muscle is damaged, as in the case of muscular dystrophies, this
enzyme leaks out of the muscle cells and gets into the blood.
A high CK blood level, therefore, suggests that the muscles
are the likely cause of the weakness rather than the nerves.
Further studies will be needed, however, to determine the exact
type of muscle disorder that is present. Carrier parents may
not have elevated serum CKs.
Since there are so many types of muscle diseases, the physician
may order a muscle biopsy to determine which is the specific
cause of a particular patient’s weakness. This biopsy involves
removal of a small piece of muscle (usually through a small
incision), typically in the area of the thigh or upper arm.
By examining this sample under the microscope, doctors gain
much information about what is happening in the muscle cells.
This may help distinguish one muscle disorder from another.
Often, the muscle is stained with special dyes to look for the
absence or presence of proteins, such as dysferlin. Finding
that a protein is abnormal (either absent or abnormal in size)
helps define the genes and proteins that are likely candidates
causing the muscle problems.
Genetic Testing
Depending on the type of LGMD that is suspected, there are laboratories
that perform clinical genetic testing and/or research genetic
testing. Genetic testing is performed by taking 2 – 6 teaspoons
of a patient’s blood. From the blood, DNA can be isolated
to allow scientists to read the DNA code in the suspected LGMD
gene to see if any alterations (mutations) are present. When
the DNA is has an alteration in it, such as a portion that is
changed or deleted, the protein that this gene codes for may
be missing or may not function properly, which leads to muscle
weakness.
Genetic testing, although informative in many cases, is still
not perfect. Infrequently, test results may be negative (that
is, mutation is found). This can mean that a laboratory missed
a subtle mutation (which is a rare event) or that a mutation
actually is not present in the gene, or that the gene suspected
to cause the given neuromuscular is not the correct gene. Test
results may also be positive (a mutation is found), or uncertain
(scientists may be uncertain of the clinical significance of
a certain alteration in a patient’s DNA).
Before one considers genetic testing either for research purposes
or for diagnostic testing, it is important to realize several
things. The decision to be genetically tested is a very important
and personal decision. It may effect your relationships, family
life, family planning, career and insurance decisions, and psychological
and emotional well-being. It is a decision to be weighed carefully.
It can have a very positive outcome (for example, when a defect
is excluded) but adverse, upsetting outcomes are also encountered
(e.g. after mutation is confirmed). Genetic counselors are available
to review the implications of genetic testing. Genetic counseling
provides useful information about the implications of the testing
and emotional support by someone with training and expertise
in the field. Genetic counselors also provide information on
prenatal testing for muscular dystrophies to see if an unborn
baby has inherited a genetic mutation. This testing can be done
if there is an affected relative in the family and a known genetic
alteration in an identified gene.
Treatment for LGMD
Currently there is no medication or cure available for LGMD
and no special dietary restrictions or additions that are known
to help in LGMD. There are, however, several options for individuals
with LGMD to preserve muscle strength.
As muscle deteriorates, a person with LGMD may develop contractures,
which are fixations of the joints. If left untreated, contractures
can become severe and cause discomfort and restricted mobility.
They can occur at any joint area, such as the knees, hips, feet,
elbows, wrists, and fingers. Contractures can be minimized or
postponed by regularly performing special exercises, as taught
by a physical therapist. Braces and surgery are other forms
of treatment.
Individuals with LGMD rarely develop spinal curvatures. This
can happen because the spine can be gradually pulled into a
curved shape from muscular weakening. There are different types
of spinal curvatures:
•scoliosis - a curve from side to side
•kyphosis - forward “hunchback” curve
•lordosis - a backward curvature in the spine, whereby
individuals walk sway-back
Severe scoliosis can be problematic if it interferes with
basic daily functions like sitting, sleeping, and breathing.
Thus, it is best if it is prevented by catching it early and
consulting a physical therapist to learn special exercises
and sitting and sleeping positions to prevent this condition.
Surgery is another option for those who develop scoliosis,
which is only rarely necessary in individuals who are severely
affected with LGMD.
Exercise therapy is recommended by some doctors for individuals
with neuromuscular disorders. However, we do not know for
sure whether exercise is good or bad for muscle diseases,
including LGMD. Occupational therapy is also helpful and focuses
more on specific activities, such as fine motor skills. The
focus is particularly on use of the hands, where the occupational
therapist can teach you ways to better perform tasks related
to your job, recreation, and daily living. Frequently, arm
supports are recommended for individuals who use a computer
frequently to prevent the arms from tiring.
At some point, an individual with LGMD may benefit from or
require a wheelchair. Many individuals initially see the wheelchair
as a sign of disability and want to postpone using it. However,
most users and their families are grateful for the wheelchair
and find they are actually more mobile, energetic and independent
than when they ambulate exclusively on weak legs.
Support
After one is confirmed to have muscular dystrophy, one may experience
overwhelming thoughts and emotions. There are several sources
of support the patient or the family members of the patient
can seek. Please use the links below to view support group and
educational information that could benefit a person with muscular
dystrophy or a family member of a person with muscular dystrophy.
Research
As more people participate in research for muscular dystrophy,
our knowledge of the mechanisms that cause these disorders will
improve. As our understanding of the disorders increases, we
will be better able to treat and manage these conditions. There
is research being done on muscular dystrophy and related muscular
disorders. Please visit Our
Research find out more about the research being done and
to stay informed about new advances.
Links Page
Muscular Dystrophy Association
www.mdausa.org
Muscular Dystrophy Campaign
www.muscular-dystrophy.org
The Muscular Dystrophy Family Foundation
www.mdff.org
To find a genetic counselor near you, please visit the National
Society of Genetic Counselors Web site.
Some content adapted from the Muscular
Dystrophy Association. For more detailed information, visit
the MDA web site at www.mdausa.org
Figure 1: Graphic used with permission of the Muscular
Dystrophy Association.
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