The molecular basis of muscular dystrophy

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The molecular basis of muscular dystrophy(?????)

• Wenya Hou
• Xue Jing
• Yitang Wang
• Jiezhong Zhang

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OUTLINE

• INTRODUCTION
• Duchenne muscular dystrophy (DMD)
• Dysfelin
• Therapeutic Approaches and perspective

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• a quarter of a million kids and adults are living
  with the disease, so chances are you may know
  someone who has it.

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What is Muscular Dystrophy?

• The muscular dystrophies (MD) are a group of more
  than 30 genetic diseases characterized by
  progressive weakness and degeneration of the
  skeletal muscles that control movement. Some
  forms of MD are seen in infancy or childhood,
  while others may not appear until middle age or
  later. Muscular dystrophies in general are a
  group of genetic, degenerative diseases primarily
  affecting voluntary muscles.

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• Healthy muscle tissue (left).
• Muscular dystrophy (right).

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HOW TO RECOGNIZE IF MUSCLE WEAKNESS IS CAUSED BY
MUSCULAR DYSTROPHY

• Mostly affects boys (rarely girls).
• Often brothers or male relatives have same
  problem.
• First signs appear around ages 3 to 5 the child
  may seem awkward or clumsy, or he begins to walk
  'tiptoe' because he cannot put his feet flat.
  Runs strangely. Falls often.
• Problem gets steadily worse over the next several
  years.

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HOW TO RECOGNIZE IF MUSCLE WEAKNESS IS CAUSED BY
MUSCULAR DYSTROPHY

• Muscle weakness first affects feet, fronts of
  thighs, hips, belly, shoulders, and elbows.
  Later, it affects hands, face, and neck muscles.
• Most children become unable to walk by age 10.
• May develop a severe curve of the spine.
• Heart and breathing muscles also get weak. Child
  usually dies before age 20 from heart failure.

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There are probably nine types of muscular
dystrophy.

• Duchenne muscular dystrophy (DMD)
• Becker muscular dystrophy (BMD)
• Emery-Dreifuss muscular dystrophy (EDMD)
• Limb-girdle muscular dystrophy (LGMD)
• Facioscapulohumeral muscular dystrophy (FSHD)
• Myotonic (pronounced my-uh-tah-nick) dystrophy
  (MMD)
• Oculopharyngeal Muscular Dystrophy (OPMD)
• Distal Muscular Dystrophy (DD)
• Congenital muscular dystrophy (CMD)

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Duchenne muscular dystrophy (DMD)

• Definition - One of nine types of muscular
  dystrophy, a group of genetic, degenerative
  diseases primarily affecting voluntary muscles.
• Cause - An absence of dystrophin, a protein that
  helps keep muscle cells intact.

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DMD

• Onset - Early childhood - about 2 to 6 years.
• Symptoms - Generalized weakness and muscle
  wasting first affecting the musclesof the hips,
  pelvic area, thighs and shoulders. Calves are
  often enlarged.
• Progression - DMD eventually affects all
  voluntary muscles, and the heart and breathing
  muscles. Inheritance - X-linked recessive. DMD
  primarily affects boys, who inherit the disease
  through their mothers. Women can be carriers of
  DMD but usually exhibit no symptoms.

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Becker muscular dystrophy (BMD)

• is similar to DMD but often much less severe.
  There can be significant heart involvement.
  Progression - Disease progresses slowly and
  with variability. Most with BMD survive well into
  mid- to late adulthood.

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Emery-Dreifuss muscular dystrophy (EDMD)

• .Cause - Mutations in the genes that produce
  emerin, lamin A or lamin C, proteins in the
  membrane that surrounds the nucleus of each
  muscle cell.
• Onset - Usually by 10 years of age.
• Symptoms - Weakness and wasting of shoulder,
  upper arm and calf muscles joint stiffening
  fainting (because of cardiac abnormalities).
• Progression - Disease usually progresses slowly.
  Cardiac complications are common and sometimes
  require a pacemaker.
• Inheritance -Can be X-linked recessive, primarily
  affecting males, who inherit the disease through
  their mothers. Another type is autosomal
  dominant, meaning it can be inherited through
  either parent an autosomal recessive type occurs
  when a faulty gene is inherited from each parent.

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Limb-girdle muscular dystrophy (LGMD)

• Definition - One of nine types of muscular
  dystrophy, a group of genetic, degenerative
  diseases primarily affecting voluntary muscles.
• Cause - A mutation in any of at least 15
  different genes that affect proteins necessary
  for muscle function.
• Onset -Childhood to adulthood.
• Symptoms - Weakness and wasting first affecting
  the muscles around the shoulders and hips (limb
  girdles).
• Progression - Usually progresses slowly, with
  cardiopulmonary complications sometimes occurring
  in later stages of the disease.
• Inheritance - Some types are autosomal dominant,
  meaning LGMD is inherited from one parent. Other
  types are autosomal recessive and occur when a
  faulty gene is inherited from each parent.

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Facioscapulohumeral muscular dystrophy (FSHD)

• Definition - One of nine types of muscular
  dystrophy, a group of genetic, degenerative
  diseases primarily affecting voluntary muscles.
• Cause - A missing piece of DNA on chromosome 4.
• Onset - Usually by age 20.
• Symptoms - Weakness and wasting of the muscles
  around the eyes and mouth, and of the shoulders,
  upper arms and lower legs initially, with later
  weakness of abdominal muscles and sometimes hip
  muscles.
• Progression - Progresses slowly with some periods
  of rapid deterioration. Disease may span many
  decad

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Myotonic (pronounced my-uh-tah-nick) dystrophy
(MMD)

• Definition - One of nine types of muscular
  dystrophy, a group of genetic, degenerative
  diseases primarily affecting voluntary muscles.
• Cause - A repeated section of DNA on either
  chromosome 19 or chromosome 3.
• Onset - Congenital form appears at birth. More
  common form may begin in teen or adult years.
• Symptoms - Generalized weakness and muscle
  wasting first affecting the face, lower legs,
  forearms, hands and neck, with delayed relaxation
  of muscles after contraction common. Other
  symptoms involve the gastrointestinal system,
  vision, heart or respiration. Learning
  disabilities occur in some cases. Congenital
  myotonic dystrophy is the more severe form.
• Progression - Progression is slow, sometimes
  spanning 50 to 60 years.
• Inheritance - Autosomal dominant the disease may
  be inherited through either the father or the
  mother.

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Oculopharyngeal Muscular Dystrophy (OPMD)

• Definition - One of nine types of muscular
  dystrophy, a group of genetic, degenerative
  diseases primarily affecting voluntary muscles.
• Cause - A faulty gene for poly(A)-binding protein
  nuclear 1 (PABPN1), which is suspected to lead to
  production of extra chemical material that causes
  formation of clumps in the muscle cells.
• Onset - Usually not until the 40s or 50s.
• Symptoms - OPMD first causes weakness of the
  muscles of the eyelids and throat weakness of
  facial and limb muscles often occurs later.
  Swallowing problems and difficulty keeping the
  eyes open are common problems.
• Progression - Slow.

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Distal Muscular Dystrophy (DD)

• Definition - A class of muscular dystrophies that
  primarily affect distal muscles, which are those
  of the lower arms, hands, lower legs and feet.
  Muscular dystrophies in general are a group of
  genetic, degenerative diseases primarily
  affecting voluntary muscles.
• Cause - A mutation in any of at least eight genes
  that affect proteins necessary to the function of
  muscles.
• Onset - childhood to adulthood
• Symptoms - Weakness and wasting of muscles of the
  hands, forearms and lower legs.
• Progression - Slow progression not
  life-threatening.
• Inheritance - May be autosomal dominant, meaning
  a faulty gene is inherited from one parent or
  autosomal recessive, occurring when a faulty gene
  is inherited from each parent.

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Congenital muscular dystrophy (CMD)

• Definition - A class of muscular dystrophies that
  show themselves at or near birth. Muscular
  dystrophies in general are a group of genetic,
  degenerative diseases primarily affecting
  voluntary muscles.
• Cause - Genetic mutations affecting some of the
  proteins necessary for muscles and sometimes for
  the eyes and/ or brain.
• Onset - At or near birth.
• Symptoms - Generalized muscle weakness with
  possible joint stiffness or looseness. Depending
  on the type, CMD may involve spinal curvature,
  respiratory insufficiency, mental retardation or
  learning disabilities, eye defects or seizures.
• Progression - Varies with type many are slowly
  progressive some shorten life span.
• Inheritance - Autosomal recessive or autosomal
  dominant these diseases are sometimes inherited
  through both parents and sometimes inherited from
  one parent . They can also occur spontaneously
  because of a newly developed genetic flaw
  (mutation).

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Duchenne muscular dystrophy (DMD)
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• ERM family

Spectrin family
e.dystrophin
?
muscular dystrophy