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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