Transcript Methods Of Treatment - Welcome to Cherokee High School

It Affects…
It Increases Chances of…
Cardiac Muscle
increase in serum
Creatine Kinase which is
a marker for muscle
damage
Skeletal Muscle
Exertional cramping and
Myoglobinuria (severe
muscular problems
Exercise intolerance
Nervous System
Schizophrenia or
related spectrum
disorders
susceptibility to
mental illnesses
mental retardation
?
?
A fault in Dystrophin leads to the
formation of a faulty protein in muscle fibers.
When Dystrophin is abnormal the muscle
fibers gradually break down and the muscles
slowly become weaker.
These Dystrophin abnormalities in muscle
provide a very good test for the diagnosis of
Becker MD.
• Several affected
males in a large
portion of people
reported by Becker
(1957) had produced
children and the
resulting pedigree
pattern was consistent
with X-linked
inheritance.
Since it is X-Linked recessive, Becker MD ONLY affects
males, but may be transmitted by unaffected female
carriers of the gene to their sons.
The sons of carriers each have a 50:50 chance of being
affected. The daughters of carriers each have a 50:50
chance of being carriers. The mothers and sisters of
affected males may be carriers and may need to be
tested. The sons of affected males do not carry the gene
and will not be affected or transmit the gene. However, all
the daughters of affected males are carriers of the gene
and may transmit the disorder to the following
generation.
Cure?
There is no cure at present
Research is proceeding to try to find a
way to induce the muscles to form
Dystrophin.
Any treatment, which may be found to be
effective in Duchenne MD, would
theoretically be effective also in the Becker
type.
Diagnosis before the age of two or three (before
symptoms are very obvious) is possible through:
A blood test - this will show very high
levels of a protein called Creatine Kinase
(CPK).
A muscle biopsy - removal of a small piece
of muscle tissue for examination. This will
show if there is a severe Dystrophin
deficiency.
Electromyography (EMG) - an examination
of muscle activity. It involves inserting a
needle into the muscle.
Human Mutation Database
Says…
The Mutation is in…
Dystrophin
Location : Xp21
Mutations in this gene were first
reported in 1987
Cause: X-Linked recessive, low
Dystrophin levels
Occurrence: 1/15000 boys
Muscle Hypertrophy: Similar to
Duchenne MD, but less severe
Onset: Appears in teens,
progressive
Weakness (Cardiomyopathy)
• May be especially prominent in quadriceps or
hamstrings
• Extreme calf pain upon exercise
• Failure to walk during the 16-80 year period
• Mental Retardation
• Varied muscle fiber size
Methods Of Treatment
Very Little Known about Human Muscle Diseases
All Patients are treated differently
Some Treated with:
Drugs, Diet, Exercise
Gene Therapy
Viral Vector/ Anti-Viral ( bacterial plasmids)
Cell Therapy
Myoblast Transplantation-Myoblasts, the precursors
of myofibers can be generated to cause the formation
of mosaic fibers which can then be used as an
alternative for low levels of Dystrophin.
Mutations/Variations in
Gene
Effect of Dystrophin Mutation on Gene Reading
Frame
Cause of Mutation: Reading
Frame Not Shifted
Result: No Stop Codons,
Produces internal deletions or
duplications of protein
Cause of Mutation: Reading frame
shifted ("Out-of-frame")
Result: Production of stop codons and
the production of small, unstable protein
with impaired membrane attachment =
absence of Dystrophin
Types of Mutations:
Deletions/Duplications
• Point Mutations- Along the entire gene
• Causes premature translation (out of frame)
• Deletions / Duplications
Location
•Majority of deletions found at the 3' end
region
•5' end deletions in 18% of cases
THESE LARGE CHROMOSOMAL MUTATIONS
CAUSE DMD AND BMD!
Types of Mutations (cont)
Nucleotide substitutions (missense / nonsense)
Nucleotide substitutions (splicing)
Nucleotide substitutions (regulatory)
Small deletions
Small insertions
Small indwells
Gross deletions
Gross insertions & duplications
Complex rearrangements (including inversions)
Repeat variations
TOTAL
122
49
0
67
26
7
93
45
2
0
411
Most prominent in children under 12 years
Left- Degeneration of several neighboring
muscle fibers
Center- Regeneration- Numerous small
rounded muscle fibers
Right- A group of intermediate sized muscle
fibers
• Increased Endomysial Connective Tissue
• Variable Fiber Size- Small Fibers are Rounded
• Internal Nuclei
Normal Dystrophin
Staining around
the rim of the
muscle fibers
Reduced
Dystrophin
Staining
Expression in Human Tissues
Contrast Through
Electrophoresis of
Duchenne/Becker MD
Lane 1- Becker MD, Dystrophin
normal in size but reduced
abundance
Lane 2- Becker MD, Dystrophin
reduced in size and abundance
Lane 3- Normal Dystrophin and
normal amount and size
Lane 4- Duchenne MD, almost no
protein present
Lane 5- Dystrophin has severely
reduced in abundance
Delivering a Boost to
Dystrophinlike Proteins
•At least two proteins have a function
similar to that of Dystrophin, and efforts
are under way to identify drugs that could
boost those proteins in Dystrophin-deficient
muscle.
•Utrophin is a small protein that looks a lot like
Dystrophin; it actually stands in for Dystrophin in fetal
muscle, but gets largely replaced and ends up in small
patches in mature muscle.
•Supported researchers have shown that
when Dystrophin-deficient mice are
genetically engineered to overproduce
utrophin or integrin, they're protected
against BMD.
C R
U E
R S
R E
E A
N R
T C
H
BMD Drugs in the
Pipeline
• The only drugs of clinically proven benefit for DMD are
Prednisone and related anti-inflammatory steroids.
•Side effects: Weight gain, loss of bone density
Albuterol — A medication that relaxes smooth muscle in the airways,
and is traditionally used to treat asthma. Two provocative studies showed
that it appears to increase strength in people without neuromuscular
disease.
Coenzyme Q10 —It's available as a dietary supplement, and might
increase the energy store available to muscle while cleaning up destructive
free radicals.
Creatine — Also involved in cellular energy production, and available as
a dietary supplement. Athletes use it to build muscle.
Gentamicin — An antibiotic that might be able to override genetic
mutations that cause protein shortening. Toxicity with prolonged exposure
may limit its use.
Glutamine — An amino acid (protein building block) that's available as
a dietary supplement. It's used by body builders, and may help those with
muscle injuries maintain or build muscle.
Oxatomide — An antihistamine used to treat hay fever. It may cut down
inflammation that contributes to muscle damage in DMD.