1. What is Duchenne Muscular Dystrophy?

Muscular dystrophy (MD) is a group of inherited muscle diseases in which muscle fibers
are unusually susceptible to damage. Muscles, primarily voluntary muscles, become
progressively weaker. In the late stages of muscular dystrophy, fat and connective tissue
often replace muscle fibers. Some types of muscular dystrophy affect heart muscles,
other involuntary muscles and other organs.

There's no cure for muscular dystrophy, but medications and therapy can slow the
course of the disease.

Signs and symptoms

Signs and symptoms vary according to the type of muscular dystrophy. In general,
muscular dystrophy symptoms may include:

• Muscle weakness
• Apparent lack of coordination
• Progressive crippling, resulting in fixations (contractures) of the muscles around
your joints and loss of mobility

Duchenne's muscular dystrophy is the most severe form of dystrophinopathy. It

occurs mostly in young boys and is the most common form of MD that affects children.
Signs and symptoms of Duchenne's MD may include:

• Frequent falls
• Large calf muscles
• Difficulty getting up from a lying or sitting position
• Weakness in lower leg muscles, resulting in difficulty running and jumping
• Waddling gait
• Mild mental retardation, in some cases

Signs and symptoms of Duchenne's usually appear between the ages of 2 and 6.
It first affects the muscles of the pelvis, upper arms and upper legs. By late
childhood, most children with this form of muscular dystrophy are unable to walk.
Most die by their late teens or early 20s, often from pneumonia, respiratory
muscle weakness or cardiac complications. Some people with Duchenne's MD
may exhibit curvature of their spine (scoliosis).

2. Provide an explanation for the symptoms experienced by this patient. Give the
significance of the elevated Creatinine Kinase levels.
3. Discuss how mutation in the dystrophin gene can lead to the development
symptoms characteristic of DMD.

Muscular dystrophy is a general term for a group of inherited diseases involving a

defective gene. Each form of muscular dystrophy is caused by a genetic mutation that's
particular to that type of the disease. The most common types of muscular dystrophy
appear to be due to a genetic deficiency of the muscle protein dystrophin.
Inheriting Duchenne's or Becker's MD
Duchenne's and Becker's muscular dystrophies are passed from mother to son through
one of the mother's genes in a pattern called X-linked recessive inheritance. Boys inherit
an X chromosome from their mothers and a Y chromosome from their fathers. The X-Y
combination makes them male. Girls inherit two X chromosomes, one from their mothers
and one from their fathers. The X-X combination determines that they are female.

The defective gene that causes Duchenne's and Becker's muscular dystrophies is
located on the X-chromosome. Women who have only one X-chromosome with the
defective gene that causes these muscular dystrophies are carriers and sometimes
develop heart muscle problems (cardiomyopathy) and mild muscle weakness. The
disease can skip a generation until another son inherits the defective gene on the X-
chromosome. In some cases of Duchenne's and Becker's muscular dystrophies, the
disease arises from a new mutation in a gene rather than from an inherited defective
gene.

Duchenne's muscular dystrophy occurs almost exclusively in boys, although it can occur
in girls. Your young child may have difficulty walking, running, rising from the floor or
climbing the stairs, or may appear clumsy and fall often. These may be early indications
of muscular dystrophy. A child with MD may learn to walk later than other children do and
may exhibit signs of muscle weakness between the ages of 2 and 6. By school age, a
child with MD may walk unsteadily and on the toes or balls of the feet. Duchenne's MD
usually results in children losing the ability to walk by age 12.

Mutations in the human dystrophin gene cause the Duchenne and Becker muscular
dystrophies. The Dystrophin protein provides a structural link between the muscle
cytoskeleton and extracellular matrix to maintain muscle integrity. Recently, Dystrophin
has also been found to act as a scaffold for several signaling molecules, but the roles of
dystrophin-mediated signaling pathways remain unknown. To further an understanding
of this aspect of the function of dystrophin, Drosophila mutants that lack the large
dystrophin isoforms were generated and their role in synapse function at the
neuromuscular junction was analyzed. In expression and rescue studies, lack of the
large dystrophin isoforms in the postsynaptic muscle cell were shown to lead to elevated
evoked neurotransmitter release from the presynaptic apparatus. Overall synapse size,
the size of the readily releasable vesicle pool as assessed with hypertonic shock, and
the number of presynaptic neurotransmitter release sites (active zones) are not changed
in the mutants. Short-term synaptic facilitation of evoked transmitter release is
decreased in the mutants, suggesting that the absence of dystrophin results in increased
probability of release. Absence of the large dystrophin isoforms does not lead to
changes in muscle cell morphology or alterations in the postsynaptic electrical response
to spontaneously released neurotransmitter. Therefore, postsynaptic glutamate receptor
function does not appear to be affected. These results indicate that the postsynaptically
localized scaffolding protein Dystrophin is required for appropriate control of
neuromuscular synaptic homeostasis (van der Plas, 2006).

Muscular dystrophy (MD) refers to a group of genetic disorders whose major symptom
is muscle wasting. There are two major forms of MD, differing in severity and age of
onset. In Duchenne muscular dystrophy, symptoms are noticeable in early childhood
and quickly become debilitating. Becker muscular dystrophy, on the other hand, is of
later onset and less severe. Both forms of MD are caused by mutations in the
dystrophin gene, a large (2.6Mb) gene comprised of 97 exons. The dystrophin protein
plays an important structural role as part of a large complex in muscle fiber membranes.
When dystrophin is missing or non-functional, the entire complex is compromised,
leading to degeneration of muscle tissue. When the ability to regenerate the muscle is
exhausted, muscle wasting occurs.

Once it was discovered that Duchenne MD and Becker MD were both forms of the same
disease, researchers attempted to determine which regions of the dystrophin gene were
most important by correlating genotype and phenotype. It was mystifying that several
large deletions were present in patients with the mild, Becker, form, while smaller
deletions were sometimes found in patients with Duchenne MD[1-4].

What seemed to be more important than the amount of coding sequence that was
deleted was whether or not the offending mutation resulted in a frameshift or not.
Researchers working on the mouse model of Duchenne MD, mdx mouse, found a
similarly puzzling result: a C-terminally truncated version of dystrophin was competent to
rescue the MD phenotype in these mice[5]. In 1988, it was entirely unclear how to
explain the apparent disconnect between genotype and phenotype.

In light of NMD, these findings are comprehensible. Becker MD patients have a

partially functional version of dystrophin that leads to less severe symptoms. Duchenne
MD patients, however, have mutations that prevent any functional dystrophin
production. Because of NMD, this includes mutations that introduce premature
termination codons.

Appreciation of the role of NMD in MD has led to improved diagnostics and promising
new treatment strategies. For example, the drug gentamicin, which causes translational
read-through of stop codons, has shown some effectiveness for restoring dystrophin
expression in cultured cells from mdx-mice[6]. Human clinical trials are currently
underway.

4. The term muscular dystrophy encompasses a number of diseases

characterized by progressive muscle wasting. How is DMD different from
Becker’s muscular dystrophy (BMD) in terms of symptamology and
prognosis?

Becker's muscular dystrophy (Benign pseudohypertrophic muscular dystrophy) is a

milder form of dystrophinopathy. Becker's muscular dystrophy is an inherited disorder
that involves slowly progressive muscle weakness of the legs and pelvis. It generally
affects older boys and young men, and progresses more slowly, usually over several
decades. Signs and symptoms of Becker's MD are similar to those of Duchenne's. The
onset of the signs and symptoms is generally around age 11, but may not occur until the
mid-20s or even later. Those affected by Becker's MD usually are able to walk through
their teens, and often well into adulthood.

Rarely, infants have this form of muscular dystrophy, in which case it's called congenital
myotonic dystrophy. The infant form is more severe, although infants with myotonic
dystrophy don't experience myotonia. Signs in infants may include:

• Severe muscle weakness

• Difficulty sucking and swallowing
• Difficulty breathing
• Cognitive impairment

Causes, incidence, and risk factors:

Becker's muscular dystrophy is very similar to Duchenne's muscular dystrophy , except

that it progresses at a much slower rate.

The disorder is inherited with an X-linked recessive inheritance pattern -- the gene is
located on the X chromosome. Since women have two X chromosomes, if one X
chromosome has the defective gene, the second X chromosome will have a working
copy of the gene to compensate. In these cases, some women have much milder
symptoms because of this ability to compensate.

Men have an X and a Y and because they don't have another X to compensate for the
defective gene, they will develop symptoms if they inherit the defective gene.

People with this disorder experience progressive muscle weakness of the legs and
pelvis, which is associated with a loss of muscle mass ( wasting ). Muscle weakness
also occurs in the arms, neck, and other areas, but not as severely as in the lower half of
the body.

Calf muscles initially enlarge (an attempt by the body to compensate for loss of muscle
strength), but the enlarged muscle tissue is eventually replaced by fat and connective
tissue (pseudohypertrophy).

Muscle contractures occur in the legs and heels, causing inability to use the muscles
because of shortening of muscle fibers and fibrosis of connective tissue. Bones develop
abnormally, causing skeletal deformities of the chest and other areas.

Cardiomyopathy (damage to the heart) does not occur as commonly with this disorder
as it does with Duchenne's muscular dystrophy. Cognitive problems may accompany the
disorder, but they are not inevitable and do not worsen as the disorder progresses.

Becker's muscular dystrophy occurs in approximately 3-6 in 100,000 male births.

Symptoms usually appear in men at about age 12, but may sometimes begin later. The
average age of becoming unable to walk is 25-30. Women rarely develop symptoms.

5. What treatment modalities may be offered in this case?

Treatment

There's currently no cure for any form of muscular dystrophy. Research into gene
therapy may eventually provide treatment to stop the progression of some types of
muscular dystrophy. Current treatment is designed to help prevent or reduce deformities
in the joints and the spine and to allow people with MD to remain mobile as long as
possible. Treatments may include various types of physical therapy, medications,
assistive devices and surgery.

Physical therapy
As muscular dystrophy progresses and muscles weaken, fixations (contractures) can
develop in joints. Tendons can shorten, restricting the flexibility and mobility of joints.
Contractures are uncomfortable and may affect the joints of your hands, feet, elbows,
knees and hips.

One goal of physical therapy is to provide regular range-of-motion exercises to keep

your joints as flexible as possible, delaying the progression of contractures, and reducing
or delaying curvature of your spine. Using hot baths (hydrotherapy) also can help
maintain range of motion in joints.

Medications
Doctors prescribe medications to treat some forms of muscular dystrophy:

• Duchenne's muscular dystrophy. The anti-inflammatory corticosteroid

medication prednisone may help improve muscle strength and delay the
progression of Duchenne's MD.

Braces can both provide support for weakened muscles of your hands and lower legs
and help keep muscles and tendons stretched and flexible, slowing the progression of
contractures. Other devices such as canes, walkers and wheelchairs can help maintain
mobility and independence. If respiratory muscles become weakened, using a ventilator
may become necessary.

Surgery
To release the contractures that may develop and that can position joints in painful ways,
doctors can perform a tendon release surgery. This may be done to relieve tendons of
your hip and knee and on the Achilles tendon at the back of your foot. Surgery may also
be needed to correct curvature of the spine.

Other treatments
Because respiratory infections may become a problem in later stages of muscular
dystrophy, it's important to be vaccinated for pneumonia and to keep up-to-date with
influenza shots.