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Duchenne Becker Muscular Dystrophy

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Palliative. Treatment. Drug Therapy: Calcium Blockers ... Current treatments are based on hypotheses are not completely effective ... – PowerPoint PPT presentation

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Title: Duchenne Becker Muscular Dystrophy


1
Duchenne /Becker Muscular Dystrophy
  • Alice Huan Xu, Christine Xiaorong Zhu, Grace Lu
    Yue, Paul Jin Lee
  • January 21, 2009

2
Muscular Dystrophy
  • Genetic, inheritable muscle disease
  • Muscles gradually weaken over time
  • Can affect many body systems (skeletal muscles,
    heart, eyes, GI system, etc.)
  • No known cure

3
Duchenne/Becker Muscular Dystrophy (DBMD)
  • DMD and BMD are variants of the same disease
  • DMD is the most common and severe form of
    muscular dystrophy
  • BMD is the less severe form
  • Together affect 1/3500-5000 newborn males

4
Cause of Disease
  • X-linked mutation that fails to make muscle
    protein dystrophin or alters the structure or
    function of it
  • Dystrophin is part of a protein complex that
    stabilizes the sarcolemma
  • 3 main hypotheses
  • Mechanical
  • Calcium
  • Inflammatory

5
Image by Lydia Kibiuk, from sfn.org
(http//www.sfn.org/index.cfm?pagenamebrainbriefi
ngs_musculardystrophy)
6
DiagnosisCreatine Kinase (CK) Test
  • A blood test
  • There are normally low levels of CK in the blood
    and high levels in muscles
  • In breakdown of the sarcolemma in DBMD, CK leaks
    out and increases its level in the blood (20-200
    times higher)
  • Very few diseases can cause such high level of CK
    in blood

7
Diagnosis Muscle Biopsy
  • Removal of a piece of muscle tissue to examine
    under a microscope

8
Skeletal Muscle Structure
  • Muscle ? Fascicle ?Fibers
  • Fibers (Muscle Cells) contain
  • 1) Sarcolemma
  • muscle cells plasma membrane
  • 2) Myofibrils
  • banded, rodlike elements which contain the
    fibers contractile machinery (ie. myosin
    actin)
  • fundamental unit sarcomere
  • 3) Costameres
  • riblike lattices on the cytoplasmic face of the
    sarcolemma
  • composed of Dystrophin-Associated Protein Complex
    (DAPC) and additional proteins

9
Dystrophin-Associated Protein Complex (DAPC)
  • DAPC is the major component of costamere
  • 1) Dystrophin physically couple force-generating
    actin filaments with sarcolemma (
    stabilization)
  • - absence (of genetic cause) lead to DMD
  • - HOW? (several hypotheses regarding MOA)
  • 2) Other proteins forming the complex reside
    mostly in the membrane, thus help to anchor the
    cytoskeleton to extracellular matrix

10
(No Transcript)
11
Pathophysiology
  • 1) Mechanical Hypothesis

12
Mechanical Hypothesis
  • Dystrophin as a molecular shock absorber in
    normal muscle fibers
  • Stabilizes sarcolemma against mechanical
    forces/stresses experienced during muscle
    contraction or stretch
  • Dampens elastic extension and recoil during rapid
    changes in muscle length
  • I. Relaxed muscle
  • II. Imposed forces will uncoil spring-
  • like elements on either side of
    non-specific
  • binding region in the middle of
    dystrophin
  • III. Electrostatic interaction between
    dystrophins
  • basic non-specific binding region
    and the
  • acidic actin filaments dampens the
    extension of
  • spring-like elements

13
Mechanical Hypothesis
  • In dystrophin-absent muscle fibers
  • Disruption of actin-sarcolemma linkage/coupling
    due to lack of DAPC formation results in
  • 1) Excessive membrane
    (sarcolemma) fragility
  • 2) Dramatic compromise of
    membrane integrity after
  • sustained contractions
  • Causes delocalization of dystrophin-associated
    proteins from the membrane which results in
  • 1) Transient holes in plasma
    membrane (sarcolemma)
  • 2) Muscle Fiber Necrosis

Muscle Weakness
Muscle Death
14
Pathophysiology
  • 2) Calcium Hypothesis

15
Calcium Hypothesis
  • In dystrophin-deficient muscle cell membranes,
    there is an influx of Ca2 through
    mechanosensitive voltage-independent calcium
    channels
  • Despite the influx, Ca2 concentrations are
    still maintained within muscle cell due to Ca2
    homeostatic mechanisms

Absence of Dystrophin in Muscle Fibers
Ca2 leak channels Abnormal Ca2 channels
? Ca2
Compensatory Mechanisms
Normal Ca2 levels
16
Calcium Hypothesis
  • If mechanical stress causes microlesions to form
    in the membrane, very high influxes of Ca2
    override the cells ability to maintain Ca2
    concentration
  • Sustained increase in Ca2 concentration leads to
    the activation of calpains which further damage
    the membrane and eventually cause muscle cell
    death

Absence of Dystrophin in Muscle Fibers
Membrane fragility Microlesions
? ? Ca2
Loss of Ca2 homeostasis
? ? ? Ca2
Calpain activation Cell membrane proteolysis
Cell death
17
Pathophysiology
  • 3) Inflammatory Hypothesis

18
Inflammatory Hypothesis
  • muscles of patients exhibit inflammatory changes
  • coordinated activity of components of the chronic
    inflammatory response observed
  • cytokine chemokine signaling
  • leukocyte adhesion diapedesis
  • invasive cell type-specific markers
  • complement system activation
  • helper T cells, cytotoxic T cells, and
    macrophages aggravate diseases
  • selective chemokine upregulation
  • key determinant in inflammatory response in
    muscle
  • this hypothesis does not explain mechanisms
    associated with cell death

19
Summary of Pathophysiology and Opportunities for
Treatment
Loss of Dystrophin orMutated Dystrophin
Treatment
Muscle weakness and death
Treatment
due to
High intracellular Ca2 levels
Inflammatory response
Mechanical damage
Treatment
Treatment
Treatment
20
Treatment
Treatment Options
Curative
Palliative
Gene Therapy
Cell Therapy
Drug Therapy
Viral Vectors
Myoblasts Stem Cells
Calcium Blockers Corticosteroids
21
Drug Therapy Calcium Blockers
  • Stabilize intracellular Ca2 by inhibiting entry
    via voltage-gated calcium channels
  • No clinical benefit in DBMD patients

Diltiazem
22
Drug Therapy Corticosteroids
  • Most commonly used drugs for DBMD
  • Reduce inflammation
  • Delay disease progression
  • Side effects bone loss and weight gain

Prednisolone
23
Conclusions
  • Although the underlying cause is known, the
    pathophysiology of DBMD is not completely
    understood
  • Current treatments are based on hypotheses are
    not completely effective
  • Therefore, effective treatments cannot be
    developed until the pathophysiology is fully known

24
References
  • Beggs, A.H., Hoffmann, E.P., Snyder, J.R.,
    Arahata, K., Specht, L., Shapiro, F., Angelini,
    C., Sugita, H., Kunkel, L.M. Exploring the
    Molecular Basis for Variability among Patients
    with Becker Muscular Dystrophy Dystrophin Gene
    and Protein Studies. Am J Hum Genet. (1991) 49
    54-67.
  • Chao, D.S., Gorospe, J.R., Brenman, J.E., Rafael,
    J.A., Peters, M.F., Froehner, S.C., Hoffmann,
    E.P., Chamberlain, J.S., Bredt, D.S. Selective
    Loss of Nitric Oxide Synthase in Becker Muscular
    Dystrophy. J Exp Med. (1996) 184 609-618.
  • Deconinck N, Dan B. Pathophysiology of Duchenne
    muscular dystrophy Current hypotheses. Pediatr
    Neurol. (2007) 361-7.
  • Ervasti, J.M. Dystrophin, its interactions with
    other proteins, and implications for muscular
    dystrophy. Biochimica et Biophysica Acta. (2007)
    1772 108-117.
  • Hoffman, E.P., Schwartz, L.. Dystrophin and
    Disease. Molec.Aspects Med. (1991) 12 175-194.
  • Voisin, V., de la Porte, S. Therapeutic
    Strategies for Duchenne and Becker Dystrophies.
    Int Rev Cytol. (2004) 240 1-30.
  • http//www.cdc.gov/ncbddd/Duchenne/

25
Summary 1
Diagnose with CK test or muscle biopsy
Duchenne Muscular Dystrophy (severe form) Becker
Muscular Dystrophy (mild form)
X-linked mutation
Loss of Dystrophin or Mutated Dystrophin
Treat with gene therapy
Muscle weakness and death
due to
High intracellular Ca2 levels
Inflammatory response
Mechanicaldamage
Treat with Ca2 channel blockers
Treat with corticosteroids
26
Summary 2
  • DMD and BMD are variants of the same disease
  • DMD is the most common and severe form of
    muscular dystrophy
  • BMD is the less severe form
  • Dystrophin as a molecular shock absorber in
    normal muscle fibers
  • Stabilizes sarcolemma against mechanical
    forces/stresses experienced during muscle
    contraction or stretch
  • Dampens elastic extension and recoil during rapid
    changes in muscle length
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