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Methods Of Treatment

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It Affects Cure? Human Mutation Database Says Methods Of Treatment Mutations/Variations in Gene Effect of Dystrophin Mutation on Gene Reading Frame Types of ... – PowerPoint PPT presentation

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Title: Methods Of Treatment


1
Becker Muscular Dystrophy
By Rachel Press
2
It Affects
It Increases Chances of
Cardiac Muscle
Nervous System
  • increase in serum Creatine Kinase which is a
    marker for muscle damage
  • Schizophrenia or related spectrum disorders
  • susceptibility to mental illnesses
  • mental retardation

Skeletal Muscle
  • Exertional cramping and Myoglobinuria (severe
    muscular problems
  • Exercise intolerance

3
?
?
The Cause...
  • 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.

4
Inheritance
X
  • 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.

5
Inheritance (cont)...
  • 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 5050 chance of
    being affected. The daughters of carriers each
    have a 5050 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.

6
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.

7
Early Diagnosis
  • 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.

8
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
9
Clinical Aspects
  • 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

10
Karyotype
11
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.

12
Mutations/Variations in GeneEffect 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

13
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!
14
Types of Mutations (cont)
Nucleotide substitutions (missense / nonsense)
122 Nucleotide substitutions (splicing)
49 Nucleotide substitutions (regulatory)
0 Small deletions 67 Small insertions
26 Small indwells 7 Gross deletions
93 Gross insertions duplications
45 Complex rearrangements (including
inversions) 2 Repeat variations
0 TOTAL 411
15
Biopsy of 10 year old boy
  • 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

16
Biopsy of a 27 year old male
  • Increased Endomysial Connective Tissue
  • Variable Fiber Size- Small Fibers are Rounded
  • Internal Nuclei

17
Dystrophin Staining
Normal Dystrophin Staining around the rim of the
muscle fibers
Reduced Dystrophin Staining
18
Expression in Human Tissues
19
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
20
Delivering a Boost to Dystrophinlike Proteins
C R U E R S R E E A N R T C
H
  • 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.

21
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.

22
THE END
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