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Muscular
dystrophy
Dr. Derakhshandeh
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Muscular dystrophy
(MD)
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a group of rare inherited muscle diseases
muscle fibers are unusually susceptible to damage
Muscles, primarily voluntary muscles, become
progressively weaker
In some types of muscular dystrophy, heart
muscles, other involuntary muscles and other
organs are affected
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voluntary & in voluntary muscles
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Duchenne's muscular dystrophy (Xp21.2)
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The types of muscular dystrophy:
 a genetic deficiency of the protein
dystrophin :
 dystrophinopathies
Duchenne's muscular dystrophy :
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the most severe form of dystrophinopathy.
It occurs mostly:
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in young boys
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Dystrophin
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a large (427 kD) cytoskeletal protein
structure with an actin-binding domain at the
amino terminus (N)
The carboxy-terminal domains associate with a
large transmembrane complex of glycoproteins
directly bind with elements of the extracellular
Dystrophin: likely plays a critical role in
establishing connections between the internal,
actin-based cytoskeleton and the external
basement membrane
Its absence may lead to increased membrane
fragility
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Dystrophin
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Duchenne's muscular
dystrophy
Difficulty getting up from a lying or
sitting position
 Weakness in lower leg muscles,
resulting in difficulty running and
jumping
 Waddling gait
 Mild mental retardation, in some
cases
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Waddling gait
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In the late stages of muscular
dystrophy, fat and connective tissue
often replace muscle fibers.
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DMD
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Orthopaedic management of patients
with Duchenne's muscular dystrophy
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Duchenne's muscular
dystrophy
X-linked inheritance
Prevalence 0.003-0.05/1,000 total
 Signs and symptoms of Duchenne's
usually appear between the ages of 2
and 5
 It first affects the muscles of the
pelvis, upper arms and upper legs.
 By late childhood, most children with
this form of muscular dystrophy are
unable to walk.
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Most die by their late teens or early
20s, often from pneumonia,
respiratory muscle weakness or
cardiac complications.
 Some people with Duchenne's MD may
exhibit curvature of their spine
(scoliosis).
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Becker's muscular dystrophy
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This type of muscular dystrophy is a
milder form of dystrophinopathy.
It generally affects older boys and
young men, and progresses more
slowly, usually over several decades.
Signs and symptoms of Becker's MD
are similar to those of Duchenne's.
The onset of the signs and symptoms
is generally later, from age 2 to 16.
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Multiplex PCR images
Iranian J Publ Health, Vol. 32, No. 3, pp.47-53, 2003
S Kheradmand kia , DD Farhud , S Zeinali , AR Mowjoodi, H Najmabadi ,
F Pourfarzad, P Derakhshandeh-Peykar
,
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-/- +/+
-/+ +/y -/+ +/y
-/- +/+
-/+ -/y +/+ +/y
Iranian J Publ Health, Vol. 32, No. 3, pp.47-53, 2003
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Iranian J Publ Health, Vol. 32, No. 3, pp.47-53, 2003
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MAPH
 Detection
of
deletions/duplication mutations
in Duchenne Muscular
Dystrophy using: Multiplex
Amplifiable Probe Hybridisation
(MAPH)
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MAPH
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Although ~95% of deletions can be detected in
males using multiplex PCR
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other methods must be used to determine
duplications, as well as the carrier status of
females
The most commonly applied methods are
quantitative multiplex PCR and quantitative
Southern blotting
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L
A
B
C
D
E
F
G
H
L
~95% of deletions can be detected in males using multiplex PCR
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MAPH
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Using high-quality Southern blots it is possible
to perform a quantitative analysis and detect
duplications
this technique is time consuming
it is difficult to exactly determine the duplication
it can be difficult to detect duplications in
females and triplications will be missed
Armour et al (Nucl.Acids Res. 2000)
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system for analysing all 79 exons of the
DMD gene for deletions and duplications
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MAPH is based on a quantitative PCR of
short DNA probes recovered after
hybridisation to immobilized genomic DNA
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1 ug of denatured genomic DNA is spotted
on a small nylon filter
hybridized overnight in a solution
containing one of the probe mixes
Following stringent washing the next day
the filter is placed in a PCR tube
and a short PCR reaction is performed
This releases the specifically-bound probes
into the solution
An aliquot of this is transferred to a second,
quantitative PCR reaction
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alterations can be examined by using a set
of short probes (140-600 bp)
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After washing and PCR the differently sized
products resolved and quantified measured
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The amount of probe amplified depends on
the number of hybridising targets and
therefore on the copy number of the
corresponding locus in the test DNA
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MAPH dystrophin probe sets a:The two
probes sets encompassing
all exons in normal individuals
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A relative comparison is made between the
band intensities or peak heights
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Applications
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areas such as cancer risk (BRCA1 and
HNPCC)
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learning disability (US: "mental retardation")
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muscular dystrophy (DMD/BMD)
neuromuscular disorders (SMA)
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Myotonic dystrophy
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Electromyogram reveals spontaneous
myotonic discharge following needle insertion
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Myotonic dystrophy
 muscular
dystrophy
 stiffness of muscles
 an inability to relax muscles at will
(myotonia)
 as well as the muscle weakness
 The inability to relax muscles at will
is found only in this type of muscular
dystrophy
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Myotonic dystrophy
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This form of MD can affect children
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It can vary greatly in its severity
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Muscles may feel stiff after using
them
Progression of this form of MD is slow
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Myotonic dystrophy
Besides myotonia, signs and symptoms of adult-onset
myotonic dystrophy may include:
Weakening of voluntary muscles
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the muscles of the feet, hands, lower legs
and arms
Weakening of head, neck and face muscles, which may
result in the face having a hollow, drooped appearance.
Weakening of muscles involved in breathing and
swallowing.
Weaker breathing muscles may result in less oxygen
intake
Weaker swallowing muscles increase the risk of
choking
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Myotonic dystrophy
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Difficulty sleeping well at night and
daytime sleepiness, and inability to
concentrate.
Clouding of the lenses of the eyes
(cataracts).
Mild diabetes .
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congenital myotonic dystrophy
 Rarely,
infants have this form of
muscular dystrophy, in which case
it's called congenital myotonic
dystrophy.
 Signs in infants include:
Severe muscle weakness
 Difficulty suckling and swallowing
 Difficulty breathing
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Myotonic dystrophy
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Correlation between Phenotype and
CTG Repeats in DM and CMyD
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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.
CTG repeat
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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The other major types of
muscular dystrophy are rare
They include:
 Limb-girdle
muscular dystrophy
 Facio-scapulo-humeral muscular
dystrophy
 Oculo-pharyngeal muscular
dystrophy
 Distal muscular dystrophy
 Emery-Dreifuss muscular
dystrophy
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Limb-girdle muscular
dystrophy (AR)
 Muscles
usually affected first:
 Hips
 Shoulders
 This
form then progresses to the
arms and legs, though progression
is slow.
 Limb-girdle MD usually begins in
the teen or early adult years.
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Limb-girdle muscular
dystrophy
AR
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Facioscapulohumeral muscular
dystrophy
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progressive muscle weakness, usually in this
order:
Face
Shoulders
Abdomen
Feet
Upper arms
Pelvic area
Lower arms
Progression of this form is slow
Onset usually occurs during the teen to
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Facio-scapulo-humeral
muscular dystrophy
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Facio-scapulo-humeral muscular
dystrophy, Ch19
5'
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Oculopharyngeal muscular
dystrophy
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drooping of the eyelids
weakness of the muscles of the eye
face and throat
resulting in difficulty swallowing
Progression is slow
Signs and symptoms first appear in
adulthood, usually in a person's 40s,
50s or 60s.
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Oculo-pharyngeal muscular
dystrophy
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Emery-Dreifuss muscular
dystrophy (AR)
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This rare form of muscular dystrophy
usually begins in the muscles of the:
Shoulders
Upper arms
Upper foots
Emery-Dreifuss MD usually begins in
the childhood to early teen years and
progresses slowly.
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Emery-Dreifuss muscular
dystrophy (AR)
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Screening and
diagnosis
A careful review of the family's
history of muscle disease can help for
a diagnosis.
 Blood tests.: Damaged muscles release
enzymes such as creatine kinase (CK)
into the blood. High blood levels of CK
suggest a muscle disease such as
muscular dystrophy .
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Screening and diagnosis
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Electromyography.: A thin-needle electrode
is inserted through the skin into the muscle
to be tested. Electrical activity is
measured as patient relax and as patient
gently tighten the muscle.
Changes in the pattern of electrical
activity can confirm a muscle disease.
The distribution of the disease can be
determined by testing different muscles .
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Genetic testing
 certain
blood tests that are used
to analyze DNA allowed some
forms of muscular dystrophy to
be diagnosed by identifying a
particular mutation of the
dystrophin gene.
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