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



Cardiac

Dilated cardiomyopathy

Arrhythmia

Shortness of breath and fatigue
Respiratory


Curvature due to contractures and muscle weakness
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
end
 Cysteine rich domain
Links to glycoprotein complex
 Central rod-like domain
Triple α-helical coiled-coil
 N-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


Recessive mutations
Females affected only if both X-chromosomes mutated

Single mutation = enough functional dystrophin produced
 Usually


from parents
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



2. Carrier female

Normal X-chromosome from father + mutated X-chromosome from mother

Normal X-chromosome = enough functional dystrophin produced
3. Unaffected male


http://mda.org/sites/default/files/X-linkedrecessive_chart.jpg
Normal X-chromosome from mother + normal X-chromosome from father
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 production
Diagnosis

Blood Creatine phosphokinase (CPK) test


Electromyography (EMG)


Measuring electric signaling to and from the muscle can rule out neurodegenerative
diseases and confirm a muscle disease.
Muscle biopsy


Damaged muscles can release creatine kinase into blood. Elevated levels signify
muscle injury: trauma or muscular dystrophy.
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


Respiratory therapy


Monitor respiratory conditions
Occupational therapy


Physical and stretching exercises help keep muscles flexible and strong
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 Summary
Overview

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-invasive
Treatment

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 prednisolone
Prednisone:

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
References
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Becker Muscular Dystrophy. Muscular Dystrophy Canada. Retrieved from http://www.muscle.ca/fileadmin/National/Muscular_Dystrophy/Disorders/Becker_E.pdf
Beenakker, E., Fock, J., Van Tol, M., Maurits, N., Koopman, H., Brouwer, O., & Van der Hoeven, J. (2005). Intermittent Prednisone Therapy in Duchenne Muscular Dystrophy: A Randomized Controlled
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Causes/Inheritance. Muscular Dystrophy Association 2014.
Damon, S., et al (2007). Prevalence of Duchenne/Becker Muscular Dystrophy Among Males Aged 5--24 Years --- Four States, 2007. Centres for Disease Control and Prevention. Retrieved from
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5840a1.htm
Ervasti, J. M. Structure and Function of the Dystrophin-Glycoprotein Complex. Madame Curie Bioscience Database 2000.
Haldeman-Englert (2014). Duchenne Muscular Dystrophy. Medline Plus. Retrieved from http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm
Learning about Duchenne Muscular Dystrophy (2013, April 18). National Human Genome Research Institute. Retrieved from http://www.genome.gov/19518854
Merlini, L., Cicognani, A., Malaspina, E., Gennari, M., Gnudi, S., Talim, B., & Franzoni, E. (2003). Early prednisone treatment in Duchenne muscular dystrophy. Muscle & Nerve, 27, 222-227.
Muscular Dystrophy (1995). Cleveland Clinic. Retrieved from http://my.clevelandclinic.org/health/diseases_conditions/hic_muscular_dystrophy
Nicolas, A. et al. Becker muscular dystrophy severity is linked to the structure of dystrophin. Human Molecular Genetics 2014; 23: 1-13.
Signs and Symptoms of Muscular Dystrophy. MDA. Retrieved from http://mda.org/disease/duchenne-muscular-dystrophy/signs-and-symptoms
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What are the treatments for muscular dystrophy? (2012, November 11). Retrieved November 16, 2014, from
http://www.nichd.nih.gov/health/topics/musculardys/conditioninfo/Pages/treatment.aspx