Transcript muscular_dystrophies_c

Muscular Dystrophies
What is Muscular Dystrophy?
(MD)
• Muscular Dystrophy is a group of genetic
disorders that cause progressive muscle
weakness.
• MD is caused by a genetic mutation. The protein
in the muscle is deformed which causes the
patients muscle to deteriorate.
• MD is characterized by degeneration and
regeneration of muscle fibers (in contrast with
static or structural myopathies) progressive
skeletal muscle weakness, defects in muscle
proteins, and the death of muscle cells and tissue
Symptoms
• Lack of coordination
• Muscle weakness
• Loss of mobility
General Diagnostic Testing
• Creatine kinase :
– greatly elevated (50 times normal)
– Increased in DMD, BMD, polymyositis, and
rhabdomyolysis
– Nonspecific if mildly elevated 2-3x normal
– Lower late in MD course due to severely
reduced muscle mass
– Not helpful for carrier detection
General Diagnostic Testing
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Electromyography
– Useful if diagnosis not clear (biopsy has
mixed features)
– Differentiates neuropathic vs. myopathic
– Characteristic myotonic discharges in
adults with myotonia – “dive bomber”
sound
– Perform after the CK
General Diagnostic Testing
• Muscle biopsy
– Dystrophic changes
include necrosis,
degeneration,
regeneration, fibrosis
and fatty infiltration,
sometimes mild
inflammation
– Specific diseases may
have inflammation,
intracellular vacuoles,
rods, and other
inclusions on biopsy
General Diagnostic Testing
• Biochemical muscle protein analysis
– Useful for specific identified protein that is
missing and many specific mutations may cause the
same deficiency
– Immunohistochemical protein staining
– Western blot – quantitates percent of normal
protein present
General Diagnostic Testing
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Genetic analysis
– PCR for specific known defects
– Southern blot for nucleotide repeats
CLASSIFICATION
• X-linked muscular dystrophy
– Duchenne muscular dystrophy
– Becker muscular dystrophy
– Emery-Dreifuss syndrome
• Autosomal recessive muscular dystrophy
– Congenital muscular dystrophy
– Limb-girdle muscular dystrophy
• Autosomal dominant muscular dystrophy
– Limb-girdle muscular dystrophy
– Fascioscapulohumeral muscular dystrophy
Differential Patterns of Initial Muscle
Weakness in MD
Duchenne MD
Emery-Dreifuss Congenital MD Limb Girdle MD
MD
FSHD
FacioScapulohumeral
OPMD
Oculopharyngeal
MD
Duchenne Muscular Dystrophy
(DMD)
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Presentation: 3-5 y/o with frequent falls,
slow running,
Prevalence of 1:3500
Etiology
– single gene defect (65% deletions in hot spot regions
, 7-10% duplications, 25% point mutations, small
deletions or insertions)
• 1/3 new mutation
• 2/3 family history
– Xp21.2 region
– absent dystrophin
Duchenne Muscular Dystrophy
(DMD)
Duchenne Muscular Dystrophy
(DMD)
• Clinical Manifestations
– Onset : age 3-6 years
– Progressive weakness
– Pseudohypertrophy of
calf muscles
– Spinal deformity
– Cardiomyopathy
– Respiratory
– 30% mild to moderate
MR
•Pseudohypertrhophy
of calf muscle,
•Tip toe gait
forward tilt of
pelvis, compensatory
lordosis
Disappearance of lordosis while sitting
GOWER’S SIGN
Duchenne Muscular Dystrophy
(DMD)
• Natural History
– Progress slowly and
continuously
– muscle weakness
– lower --> upper
extremities
– unable to ambulate:
10 year (7-12)
– death from
pulmonary/ cardiac
failure: 2-3rd decade
Duchenne Muscular Dystrophy
Diagnosis
Clinical Signs (Gower’s Sign)
Family history (pedigree analysis)
Increase CPK (200x)
DNA mutation analysis (65%) or haplotype
analysis)
• Myopathic change in EMG
Bx: m. degeneration
• Muscle biopsy and Immunoblotting:
Absence dystrophin (if geneticist can’t
find the mutation !!)
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Prenatal diagnosis is available
Becker Muscular Dystrophy
(BMD)
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Slowly progressive form with same gene affected as
Duchenne MD
Etiology
– single gene defect
– short arm X chromosome
– altered size & decreased amount of dystrophin
Muscle biopsy immunostaining for dystrophin with
patchy staining
Disorder of function or decreased amount of
dystrophin rather than absence of the protein
DMD / BMD
Emery-Dreifuss Muscular Dystrophy
(EDMD)
Presentation: This disorder is characterized by a
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triad
Early contractures of the Achilles tendon, elbows and
posterior cervical muscles
Slowly progressive muscle wasting and weakness with a
humeroperoneal distribution
Cardiomyopathy arises , which usually presents as cardiac
conduction defects.
Genetics
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X-linked type affects emerin (STA gene at chromosome
Xq28)
• Diagnose by protein analysis of leukocytes or skin
fibroblasts
• DNA testing available
AD affects lamin A or lamin C (chromosome 1q21)
Congenital Muscular Dystrophy
(CMD)
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Presentation: neonatal onset of severe weakness,
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Classification
delayed motor milestones, contractures
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Merosin-negative
Merosin-positive
Neuronal migration
• Fukuyama
• Muscle eye-brain
• Wlaker-Warburg
Limb Girdle Muscular Dystrophy
(LGMD)
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Presentation: variable age of onset with
weakness and wasting of the limb-girdle
15 genetically different types (genetical and
clinical heterogenic)
AD forms are rare but more less severe
than AR forms
Several of these disorders are associated
with clinically significant cardiac involvment
Type
Protein
Chromosome
Inheritance
1A
Myotilin
5q22-34
AD
1B
Laminin A/C
1q21
AD/allelic to EDMD
1C
Caveolin-3
3p25
AD
7q
AD
1D
2A
Calpain-3
15q15-21
AR
2B
Dysferlin
2p13
AR/allelic to Myoshi
Myopathy
2C
Gamma
sarcoglycan
13q12
AR
2D
Alpha sarcoglycan
17q12-21
AR
2E
Beta sarcoglycan
4q12
AR
2F
Delta sarcoglycan
5q33-34
AR
2G
Telethonin
17q11-12
AR
9Q33
AR
19q13
AR/allelic to CMD 1C
2H
2I
Fukutin-related
protein
FascioScapuloHumeral Muscular
Dystrophy (FSMD)
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Presentation:
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Facial and shoulder girdle are first affected
muscle group
Later foot extensors and pelvic girdle muscles
become involved
The heart is not implicated in most cases.
mild high pitched hearing loss, retinal
abnormalities, mental retardation in early onset
Genetics/Testing
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Southern blot testing available (chromosome
4q35) for decrease in repeats normally present
Muscle biopsy may show lymphocytic infiltrates
Oculopharyngeal Muscular Dystrophy
Presentation:
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mid-adult with ptosis, facial muscle weakness
with difficulty swallowing, proximal muscle
weakness, may have extraocular muscle
weakness, more common in French-Canadian and
Hispanic population
Genetics
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Affects poly A binding protein 2 (PABP2) by
expansion of a GCG repeat without anticipation
seen – Southern blot (chromosome 14q11-13)
Myotonic Dystrophy (DM)
Presentation – adult with
multiple systems affected
– Primarily distal and
facial weakness
– Facial features: frontal
balding in men, ptosis,
low-set ears, hatchet
jaw, dysarthria, swan
neck, ^ shaped upper lip
– Myotonia: worse in cold
weather, after age 20
– Heart: conduction block
– evaluate syncope
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Smooth muscle: constipation, care with
swallowing, gallstones, problems with childbirth,
BP lability
Brain: learning disabilities, increased sleep
requirement
Ophthalmology: cataracts
Endocrine: insulin resistance, hypothyroidism,
testicular atrophy
Myotonic Dystrophy
• Genetics
• Myotonic dystrophy is caused by a triple
nucleotide (triplet) expansion (CTG) in the
noncoding region of the myotonin gene at
chromosome 19q13.3.
• The condition is characterized by extreme
variability, anticipation and differential
expansion in the maternal and paternal
germline.
– 4-37 repeats Normal
– >50 repeats Affected
Myotonic Dystrophy (DM)
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Congenital: severe form
– initial respiratory distress after birth
with ventilatory requirement or apnea,
– feeding difficulty,
– mental retardation,
– club feet, scoliosis,
– strabismus
Huntington Disease (HD)
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Presentation
Mood Swings
Impaired cognitive functions
Chorea
Huntington’s Disease is an Autosomal Dominant “Trinucleotide Repeat” Disorder caused by a mutation of a gene on
the 4th chromosome which is responsible for producing the
protein Huntingtin, that creates excess copies of the CAG
codon which genetically program the degeneration of the
neurons of the brain.
Age of onset is found generally in adults around the age of 40
but varies based on the number of repeats.
The earliest onset of Huntington’s ever documented was a two
year old boy who was found to have nearly 100 CAG repeats.
The symptoms of HD can also develop at 55 or later, in which
case it is harder to recognize.
Huntington Disease (HD)
The number of CAG codons varies and so does the
severity of the disease
– >40 repeats you develop HD, children 50% chance
of developing disease
– 36-39 repeats “Grey Zone” May develop HD,
children may or may not develop HD
– 29-35 repeats the individual will not develop HD,
children may
– <29 repeats, the individual will not develop HD,
children will not develop HD
Summary
Clinical
DMD
LGMD
FSMD
CMD
Incidence
common
less
Not
common
Rare
Age of onset 3-6 y
2nd decade
2nd decade
At/ after
birth
Sex
Male
Either sex
M=F
Both
Inheritance
Sex-linked
recessive
AR, rare AD
AD
Unknown
Muscle
involve.
Proximal to
distal
Proximal to
distal
Face &
shoulder to
pelvic
Generalized
Muscle
spread until
late
Leg, hand,
arm, face,
larynx,eye
Upper ex,
calf
Back ext,
hip abd,
quad
-
Summary
Clinical
DMD
LGMD
FSMD
CMD
Pseudo
hypertrophy
80%
calf
< 33%
Rare
No
Contracture
Common
Late
Mild, late
Severe
Scoliosis
Kyphoscoliosis
Common,
late
Late
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?
Heart
Hypertrophy
tachycardia
Very rare
Very rare
Not
observed
Intellectual
decrease
Normal
Normal
?
Course
Stead, rapid
Slow
Insidious
Steady
Treatment
• There is no cure for MD
• Medications that are prescribed for MD
patients
• Steroids
• Braces for support
• Mobility chairs
• Surgery is also an option to release
contractures
STEM CELL THERAPY !!!!?