Duchenne Becker Muscular Dystrophy

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Duchenne /Becker Muscular Dystrophy

• Alice Huan Xu, Christine Xiaorong Zhu, Grace Lu
  Yue, Paul Jin Lee
• January 21, 2009

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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

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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

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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

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Image by Lydia Kibiuk, from sfn.org
(http//www.sfn.org/index.cfm?pagenamebrainbriefi
ngs_musculardystrophy)
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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

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Diagnosis Muscle Biopsy

• Removal of a piece of muscle tissue to examine
  under a microscope

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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

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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

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Pathophysiology

• 1) Mechanical Hypothesis

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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

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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
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Pathophysiology

• 2) Calcium Hypothesis

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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
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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
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Pathophysiology

• 3) Inflammatory Hypothesis

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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

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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
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Treatment
Treatment Options
Curative
Palliative
Gene Therapy
Cell Therapy
Drug Therapy
Viral Vectors
Myoblasts Stem Cells
Calcium Blockers Corticosteroids
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Drug Therapy Calcium Blockers

• Stabilize intracellular Ca2 by inhibiting entry
  via voltage-gated calcium channels
• No clinical benefit in DBMD patients

Diltiazem
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Drug Therapy Corticosteroids

• Most commonly used drugs for DBMD
• Reduce inflammation
• Delay disease progression
• Side effects bone loss and weight gain

Prednisolone
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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

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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/

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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
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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