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DUCHENNE
MUSCULAR DYSTROPHY
By Jade
Cognetti
 OVERVIEW
Duchenne
muscular dystrophy (DMD) is the
most frequently occurring muscular dystrophy
disease, affecting as many as 1 in 3,500
male births worldwide (Krag,
Bogdanovich, Jensen, Fischer, Hansen-Schwartz,
Javazon, Flake, Edvinsson, and Khurana,
2004). It is also one of the
most rapidly progressing childhood neuromuscular
disorders (Muscular
Dystrophy Australia [MDA], 2009).
DMD is characterized by a progressive
weakening and wasting of the skeletal
muscles that control movement, which
is caused by an absence of dystrophin,
a protein necessary to maintain muscle
integrity.
Currently,
there is no specific cure to stop or
reverse any form of DMD, and few people
with DMD live past 30 years of age (Krag,
et al., 2004). There are, however,
available treatments to minimize the
effects of the disease and preserve
muscle strength. People with DMD are
now estimated to have a 53% chance of
living until 25, which is an increase
from 0% in 1960 (Eagle,
Baudouin, Chandler, Giddings, Bullock,
and Bushby, 2002). Advances towards
a cure are in process as the culpable
gene has already been discovered and
human clinical trials are currently
under way (MDA,
2009).
CAUSES
AND INHERITANCE PATTERNS
DMD is caused
by a gene alteration, or mutation, that
normally codes for the muscle protein
dystrophin.
Without this gene, people (usually boys)
are unable to produce the dystrophin
protein in their muscles, resulting
in progressive weakening (National
Human Genome Research Institute [NHGRI],
2009). The onset is usually between
3 and 5 years of age, but may appear
as early as infancy. The disorder progresses
rapidly and most children are unable
to walk by the age of 12 (National
Institute of Neurological Disorders
and Strokes [NINDS], 2009).
The DMD gene
is the second largest gene to date,
and is inherited X-linked recessively.
The implication of this inheritance
pattern accounts for the greater susceptibility
among boys. Males who inherit the gene
are destined to have the disorder since
they can only pair the DMD X chromosome
with a Y chromosome; there is no second
chance to back up their dystrophin production.
If this male produces children, all
his daughters would be carriers and
none of his sons would be affected (NHGRI,
2009).
Although
females may be a "carrier"
of DMD (possessing one defective copy
of the DMD on an X chromosome), they
have a second X chromosome that serves
as a back up and is able to produce
dystrophin protein. Most carriers are
unaware that they even possess this
"changed" gene, however approximately
20% will show some DMD-like symptoms,
including muscle weakness and cardiac
abnormalities. Although carriers do
not actually have DMD, they have a 50%
chance of passing on the disorder with
each pregnancy (NHGRI,
2009).
Due to genetic
mutation, the disease may also appear
in families with no known history of
DMD, referred to as de
novo change. About 10% of DMD cases
are caused by gonadal
mosaicism which refers to a condition
where an individual has two or more
populations of cells with different
genotypes in their eggs or sperm (NHGRI,
2009).
SYMPTOMS
& DIAGNOSIS
Typically,
the first noticeable symptom of DMD
is a delay in motor milestones. The
child may not be able to sit or stand
independently, and walking occurs later
than the average age (around 18 months
for children with DMD). The child also
usually exhibits difficulty with rising
and climbing stairs, and walking gait
may be described as waddling (University
of Maryland Medicine [UMM], "Duchenne,"
2003). The lower half of the
body is affected earlier and more severely
than the upper half (NHGRI,
2009), and one of the chief diagnoses
for DMD is referred to as Gower's
Sign (Stopka
& Todorovich, 2008). Because
of weak anti-gravity muscles, Gower's
Sign is evidenced by a child's inability
to push himself erect; he will walk
his hands towards his feet, and then
up the legs and thighs to achieve a
standing position.
Between the
ages of 6 and 11, the child generally
experiences a steady degeneration in
muscle strength, subsequently affecting
posture and mobility. This is most evident
on inclines (UMM,
"Duchenne," 2003).
Abnormal bone development may also lead
to skeletal deformities of the spine
causing lordosis,
which is an exaggerated forward curve
of the lower back. By age 10, most require
braces for walking, and by age 12, weakening
has progressed such that most are confined
to a wheelchair. Children with DMD also
frequently encounter breathing difficulties;
cardiomyopathy
occurs in almost all cases by the age
of 18, and breathing complications are
common causes of death (NHGRI,
2009).
Although
intellectual impairment is rare in boys
with DMD, is does appear more frequently
than in other children (UMM,
“Duchenne,” 2003).
This handicap does not worsen as the
disorder progresses (NHGRI,
2009).
There are
a number of ways to diagnose DMD. To
detect the disorder early-on, clinicians
may find the child has progressive symmetrical
muscle weakness or is exhibiting Gower's
Sign, as explained earlier. Additionally,
caretakers will note abnormal clumsiness
or weakness, and muscles that tend to
pseudohypertrophy
as muscle protein is replaced by water,
connective tissue, and fat (Stopka
& Todorovich, 2008).
A muscle
biopsy can be performed to test for
abnormal levels of dystropin.
Boys with Duchenne will appear to have
an absence of "caulking" around
muscles cells, an evidence of dystropin
deficiency. As an alternative to performing
the biopsy, blood samples can be used
for genetic testing. Current methods
of genetic testing examine gene deletion/duplication
and sequencing, however these tests
are not able to examine all areas of
the gene. Because of this shortcoming,
a muscle biopsy is the only method that
can detect the level of dystropin for
certain (NHGRI,
2009).
Blood sample
tests that detect levels of creatine
kinase are also able to confirm
the disease. Creatine kinase (CPK) is
an enzyme normally present in high concentrations
within muscles cells. As the muscles
break down, cell membranes become unusually
permeable and muscle contents leak out
into the bloodstream. Blood CPK levels
that are 25-30X normal levels generally
indicate DMD (Stopka
& Todorovich, 2008). Many
individuals confirm diagnosis through
a combination of methods including family
history, blood creatine kinase concentration,
and muscle biopsy with dystrophin studies
(NHGRI, 2009).
DRUG
TREATMENT & THERAPIES
As there
is currently no cure, treatment for
DMD is aimed at confronting the symptoms.
Drug therapy utilizes corticosteroids
to slow degeneration, anticonvulsants
to control seizures and abnormal muscle
activity, immunosuppressants
to delay damage to degenerating muscle
fibers, and antibiotics to combat respiratory
infection (NINDS,
2009). The steroid medication,
prednisone,
is given to improve strength and function.
While it has been shown to prolong the
ability to walk, it often generates
undesirable side effects including weight
gain, high blood pressure, behavior
changes, and delayed growth. Several
other drug therapies are under investigation,
including those similar to prednisone
but with fewer side effects (NHGRI,
2009).
Many individuals
benefit from a combined effort of occupational
therapy, physical therapy, and assistive
technology. Assisted ventilation is
common for respiratory weakness, and
some may require a pacemaker (NINDS,
2009). Surgery may be required
for severe contractures or scoliosis
(NHGRI, 2009).
EXERCISE
THERAPY
Although
initially counter-intuitive, exercise
benefits persons with DMD for many reasons.
Those who suffer from Duchennes often
encounter contractures of the hip
flexors and plantar
flexors. "Contractures are
a tightening of the muscle and tendons,
which limit the full range of motion
in a joint"
(Parent Project Muscular Dystrophy [PPMD],
2008, “What are contractures?”).
Because contractures results from a
disproportionate tightening of the muscles
- as they lose strength at difference
times and paces - a flexibility program
is imperative in reducing the progression
of these contractures and ensuring maintenance
of an upright posture (PPMD,
2008).
Therapists
advocate flexibility as the primary
focus of any exercise program for people
with DMD, but warn to avoid any ballistic
stretching that can cause muscle
tissue damage. A program composed of
passive and active stretching, with
gentle pressure at the end of the range,
will help ensure full joint mobility
while minimizing risk of contractures.
Stretches should be performed 3-4 times
daily and focused on muscle groups prone
to contractures: hips, shoulders, knees,
wrists, fingers, and plantar flexors
(National Center on Physical Activity
and Disability [NCPAD], 2009).
As DMD progresses
and loss of ambulation occurs, the reduction
in caloric expenditure often leads to
obesity. Combined with a loss of strength,
people with DMD may contract pressure
sores (warning:
link leads to very graphic photos) due
to an inability to perform push-ups
and pressure release exercises. Tolerated
endurance exercises allow the person
to increase energy expenditure and ward
off obesity (NCPAD,
2009). Endurance training should
be coupled with individualized advice
from doctors or dieticians to manage
nutritional status. It is important
to note that eating more protein will
not have any effect on the lack of protein
present in the muscles (MDA,
2009).
Recommendations
for persons with DMD encourage walking
at speeds and distances as tolerated
by the individual. Surfaces should be
level to avoid changes in directional
velocity that tend to promote muscle
damage. Ballistic
and dynamic
constant external resistance exercise
is also contraindicated
(NCPAD, 2009).
Cycling and swimming are suggested as
ideal endurance activities for this
population, which enhance physical,
social, and emotional development while
strengthening gross motor skills (PPMD,
2008).
As mentioned
earlier, persons with DMD are prone
to posture complications. Thoracic
s-curve deformity affects two-thirds
of boys within a couple years of losing
ambulation; a distortion that can then
interfere with respiration and may eventually
cause death. Strengthening of postural
muscles is critical in reducing muscle
atrophy of the spine and deterring scoliosis.
Because of the damaging effects often
induced by strength exercises, it is
difficult to establish a clear muscle
strength guideline. It is hypothesized
that only concentric
isokinetic
or only eccentric
isokinetic
exercises - but not both at the
same time - may benefit individuals
with DMD (NCPAD,
2009).
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about the author, Jade
Cognetti:
Jade graduated from
the University of Florida in 2009 with
a B.S. in Health Education & Behavior
as well as a B.A. in Spanish. She is
currently applying to master's degree
programs in Human Genetics, and hopes
to work within the public health arena.
Her interests include science, travel,
learning foreign languages, and coaching
lacrosse. |
