X-linked Muscular Dystrophy Sonja Li, Nancy Liu, Yu Chen Amy Sung, Michelle Tam M142 Fall 2014 structor: Dr. Jeffrey Henderson
Dec 15, 2015
X-linked Muscular Dystrophy
Sonja Li, Nancy Liu, Yu Chen Amy Sung, Michelle Tam
PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson
What is muscular dystrophy?
Genetic disease affecting skeletal muscles
Characterized by progressive muscle weakness and wasting, and loss of motor skills
X-linked recessive most common: Duchenne and Becker
More than 1 in 3500 males born
Onset age from infancy to adulthood
Most end up wheelchair-bound
Duchenne muscular dystrophy
Most common type: 1 in 3500
Early onset: signs appear before 6 years of age
Delayed development of motor skills
Weakness/fatigue
Difficulty in keeping balance
Pseudohypertrophy
Contractures
Wheelchair dependent by ~12 years of age
DMD - Gower Maneuver
Becker muscular dystrophy
Milder form of Duchenne
1 in 18,518 males
Onset age: 5 to 15 years of age
Loss of muscle mass and motor skills
Weakness/fatigue
Pseudohypertrophy
Contractures
Wheelchair dependent by 25-30
Other Conditions Caused
Scoliosis
Curvature due to contractures and muscle weakness
Cardiac
Dilated cardiomyopathy
Arrhythmia
Shortness of breath and fatigue
Respiratory
Progressive weakening of the diaphragm
Cognitive (non-progressive)
Dystrophin Predominant DMD transcript in striated muscle
Gene mutations, deletions or duplications result in a loss of expression
Rod shaped, cytoplasmic
Forms dystrophin-glycoprotein complex (DGC)
http://upload.wikimedia.org/wikipedia/commons/6/64/PBB_Protein_DMD_image.jpg
Dystrophin Domains
C-terminal endCysteine rich domain
Links to glycoprotein complexCentral rod-like domain
Triple α-helical coiled-coilN-terminal actin binding domain
Dystrophin-Glycoprotein Complex• Serves as a link b/w extracellular matrix and
subsarcolemmal cytoskeleton• Protects the sarcolemma against stress during
muscle contraction or stretch• Dystroglycan: interacts with Cys-rich domain
and EC matrix• Syntrophin: directly binds to dystrophin C-
terminus• Sarcoglycan complex: subcomplex of four
single transmembrane glycoproteins
Normal Muscle Duchenne Muscular Dystrophy
• Degeneration in DGC leads to tearing of sarcolemma, causing a disturbance in CK and Ca2+ concentrations
Causes of Muscular Dystrophy Muscular dystrophy = mutation of DMD gene
Inability to produce functional dystrophin protein
Constant muscle contraction and relaxation → weaken + destroy muscles
Two types of muscular dystrophy
1. Becker muscular dystrophy – inability to produce functional dystrophin
Dystrophin – not 100% non-functional
Limited function → less severe
2. Duchenne muscular dystrophy – inability to produce dystrophin
No dystrophin production/production of only non-functional dystrophin
No function → more severe
Causes of Muscular Dystrophy
Main cause = parents
X-linked disease – caused by mutation in X-chromosome
Inherited from parents
Recessive mutations
Females affected only if both X-chromosomes mutated
Single mutation = enough functional dystrophin produced
Usually unaffected → carrier of disease
Double mutation = affected, but unlikely
Males – single X-chromosome
Mutation in X-chromosome = no dystrophin production
Inheritance of Muscular Dystrophy Unaffected carrier mother + unaffected father
Mother = 1 mutated X-chromosome + 1 normal X-chromosome
Father = 1 normal X-chromosome + 1 normal Y-chromosome
1. Unaffected female Normal X-chromosome from mother + normal X-chromosome from father
2. Carrier female Normal X-chromosome from father + mutated X-chromosome from
mother
Normal X-chromosome = enough functional dystrophin produced
3. Unaffected male Normal X-chromosome from mother + normal Y-chromosome from father
4. Affected male Mutated X-chromosome from mother + normal Y-chromosome from
father
No normal X-chromosome = no dystrophin productionhttp://mda.org/sites/default/files/X-linked-recessive_chart.jpg
Diagnosis
Blood Creatine phosphokinase (CPK) test
Damaged muscles can release creatine kinase into blood. Elevated levels signify muscle injury: trauma or muscular dystrophy.
Electromyography (EMG)
Measuring electric signaling to and from the muscle can rule out neurodegenerative diseases and confirm a muscle disease.
Muscle biopsy
The microscopic analysis of a sample of muscle tissue can identify presence of muscular dystrophies and its form.
Genetic testing
Testing of mutations in muscular dystrophy related genes can determine the exact form of muscular dystrophy.
Therapies for Muscular Dystrophy
Physical therapy
Physical and stretching exercises help keep muscles flexible and strong
Respiratory therapy
Monitor respiratory conditions
Occupational therapy
Teach use of assistive devices eg. wheelchairs
Corrective surgery
For certain conditions from muscular dystrophy
eg. pacemaker for myotonic muscular dystrophy or heart problems
Drug therapy for Duchenne Muscular Dystrophy
No known cure
Drugs effective only in transiently alleviating the symptoms, delaying muscle degeneration and increasing force of strength
Two most common are corticosteroids: deflazacort and prednisone
Both suppress the body’s immune system and release substances which cause inflammation
Mechanisms unknown
Prednisone
Common dose is 0.75 mg/kg of body weight per day
Increases utrophin and dystrophin protein expression in some dystrophic muscles to increase muscle strength
Helps increase number of regenerating fibers after injury of skeletal muscle (prone to occur in patients with DMD)
By increasing myoblast and myotube density as well as number of proliferating myoblasts
General effect: loss of ambulation postponed to mid-teens or twenties and better preservation of respiratory and cardiac function
Side effects: weight gain, rounded face (Cushingoid appearance), acne, cataracts, GI symptoms and behavioural changes
X-Linked Muscular Dystrophy SummaryOverview Duchenne and Becker muscular dystrophy: most common forms of muscular dystrophy; affects skeletal muscles and cardiac muscles, leading to their degeneration. Signs and symptoms include: muscle weakness, loss of muscle coordination and balance, pseudohypertrophy, contractures, and Gower’s sign. Duchenne is more severe, with earlier onset age and quicker progression, while Becker is like a milder form of Duchenne. Affected patients gradually loses muscle mass and mobility, end up wheelchair bound and have increased motility Other conditions caused as a consequence of Duchenne and Becker: Scoliosis, Dilated cardiomyopathy, respiratory complications, and cognitive impairments (which
unlike other symptoms, is non-progressive)Dystrophin Mutations, deletions or duplications of the dystrophin gene most frequently result in a loss of dystrophin expression in muscle of patients afflicted with DMD Consists of 4 domains:
C-terminal end – binds to syntrophin Cysteine rich domain – links the cytoskeleton to the extracellular matrix via the membrane with dystrophin-associated glycoprotein, dystroglycan Central rod-like domain – made from a triple α-helical coiled-coil N-terminal actin binding domain (very short)
Dystrophin works to protect the sarcolemma against stress through a dystrophin-glycoprotein complex Includes dystroglycan, syntrophin, and sarcoglycan complex Degeneration in DGC leads to tearing of sarcolemma, causing a disturbance in CK and Ca2+ concentrations
Causes Muscular dystrophy = recessive genetic mutation in X-chromosome → inherited from parents (most likely mother)
Females – affected if only both X-chromosomes mutated → far less likely to have dystrophy Males – single mutation required (only one X-chromosome) → most cases of muscular dystrophy are males
Diagnosis Ways to diagnose muscular dystrophy include: Blood Creatine phosphokinase/CPK test, EMG test, biopsy, and genetic testing, which is most specific and non-invasiveTreatment Various therapies available to alleviate symptoms of muscular dystrophy include physical, respiratory, speech, occupational and drug therapies. Drug treatments for Duchenne Muscular Dystrophy:
There is no known cure – medication only helps to alleviate symptoms and delay muscle degeneration Most common drug used is prednisone, which is a corticosteroid
Active form is prednisolonePrednisone: Increases utrophin and dystrophin protein expression in some dystrophic muscles – increases muscle strength Helps increase number of regenerating fibers after injury of skeletal muscle by increasing myoblast and myotube density as well as number of proliferating myoblasts General effect: loss of ambulation postponed to mid-teens or twenties and better preservation of respiratory and cardiac function Side effects: weight gain, rounded face (Cushingoid appearance), acne, cataracts, GI symptoms and behavioural changes
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