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Molecular Basis of Disease > Muscular dystrophy > Flashcards

Muscular dystrophy Flashcards

1
Q

What type of muscle is skeletal muscle?

A

Voluntary

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2
Q

How many muscles are found in the body?

A

640

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3
Q

What are the main functions of muscles?

A

Posture

Locomotion

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4
Q

Muscles are able to regenerate

TRUE or FALSE

A

TRUE

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5
Q

What is the stem cell found in muscle called?

A

Satellite cell

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6
Q

What is the smallest unit of muscle?

A

Myofibrils

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7
Q

What is a collection of myofibrils called?

A

Fascicles

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8
Q

What is the layer of connective tissue that surrounds the fascicles called?

A

Perimysium

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9
Q

What is the layer of connective tissue that surrounds each individual muscle fibre?

A

Endomysium

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10
Q

What is the plasma membrane of the muscle fiber called?

A

Sarcolemma

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11
Q

What is the cytoplasm of the muscle fiber called?

A

Sarcoplasma

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12
Q

What is the name of the endoplasmic reticulum of the muscle fiber called?

A

Sarcoplasmic reticulum

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13
Q

What is the role of the endoplasmic reticulum?

A

Stores, releases and retrieves calcium ions

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14
Q

What is the name of the functional unit of a skeletal muscle fibre?

A

Sarcomere

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15
Q

Describe the divisions of muscle

A

Sarcomere

Myocytes

Fascicles

Muscle

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16
Q

What type of nuclei are found in cells composing skeletal muscle?

A

Post-mitotic nuclei

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17
Q

Is skeletal muscle innervated?

A

Yes

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18
Q

Is skeletal muscle vascularised?

A

Yes

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19
Q

What is muscular dystrophy?

A

Inherited disorder where strength and muscle bulk gradually decline

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20
Q

What are the different conditions of muscular dystrophy?

A

Duchenne muscular dystrophy

Becker muscular dystrophy

Emery-Dreifuss muscular dystrophy

Limb-girdle muscular dystrophy

Facioscapulohumeral muscular dystrophy

Myotoic dystrophy

Oculopharyngeal muscular dystrophy

Congenital muscular dystrophy

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21
Q

What characterises the different muscular dystrophies?

A

Different mutations to the gene coding for the protein complex

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22
Q

What are the differences in presentation between the different muscular dystrophy types?

A

Different types of muscle affected

Different severity in symptoms

Different onset

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23
Q

Describe the appearance of normal muscle

A

Fibres are polyglonal

Fibres are tightly packed

Fibres show little variation in size

Nuclei of muscle cells are found on the edge

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24
Q

Describe the appearance of muscle in MD patients

A

Cells are characterised by necrosis and fibrosis

Diffuse variation in size

Deposition of adipose tissue

Inflammation

Regeneration observed as small cells with large nuclei

More nuclei internally

Abnormal cells with whorled appearances

Split fibres

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25
You can diagnose the type of MD by muscle biopsies TRUE or FALSE
FALSE
26
What cells do MD pathologies affect?
Muscle fibres Satellite cells Extracellular matrix Inflammatory cells Fibroadipogenic cells
27
What is the consequence of extracellular matrix defects in MD?
Dysfunction in the extracellular matrix consequently affects - satellite cell niche - signalling - physical barrier to stem cells
28
What is the dystrophin-associated complex?
Protein that spans the cell membrane and whose mutations at different parts of the complex cause different MD pathologies
29
Which part of the dystrophin-associated complex is affected in DMD?
Dystrophin
30
Which part of the complex is affected in Becker MD?
Dystrophin
31
Which part of the complex is affected in Emery-Dreifuss MD?
Emerin Lamin
32
Which part of the complex is affected in Limb-girdle MD?
Sarcoglycans
33
What does DMD stand for?
Duchenne Muscular Dystrophy
34
What is DMD?
Progressive, muscle-wasting neuromuscular disorder
35
What proportion of the population is affected by DMD?
1 in 5000 newborn boys
36
Describe the pathogenesis of DMD
Deficit in dystrophin causes muscle cell death upon contraction Muscle undergoes successive rounds of degeneration and regeneration Eventually the muscle tissue is replaced by fibrotic tissue
37
Why is muscle replaced by fibrotic tissue in DMD?
The muscle regeneration cannot keep up with the degeneration
38
At what age do patients with DMD lose ambulation?
10-12 years
39
At what age do patients with DMD die?
Early adulthood (25-30 years) Advances in treatment have increased the survival in patients
40
What is the best way to monitor a treatment for MD patients?
Ambulatory assessment
41
What is an ambulatory assessment?
6 minute walking test
42
What is fibrotic tissue composed of?
Fat Connective tissue
43
What causes the loss of stem cells in muscle of DMD patients?
Not known Are they lost via apoptosis Does the pathological environment cause them to not work correctly
44
What is the main difference between Becker MD and DMD ?
Becker is a milder variant of DMD
45
What makes Becker MD a milder condition than DMD?
Later onset Progression of the disease is variable Loss of walking ability is only seen in 18% of cases Scoliosis is very uncommon
46
What mutation causes Becker MD?
Deletion mutations that lead to misshapen dystrophin Still maintains the reading frame Loss of amino acids that are not essential to dystrophin function Dystrophin produced is functional but still semi-functional
47
What mutation cause DMD?s
Frameshift mutation that cause translation to end earlier on the gene Loss of amino acids that are essential to dystrophin function No functional dystrophin is produces
48
What is the role of dystrophin?
Attaches the dystrophin associated protein complex to the actin of the ECM Prevents the myocyte cell membrane from ripping apart during the contraction of muscles
49
What makes the discovery of the dystrophin gene unique?
The gene was discovered before the protein
50
Where is the dystrophin gene localised?
xp21
51
What causes the different isoforms of dystrophin found around the body?
Different promoter sequences Code for different lengths of dystrophin needed in different parts of the body
52
What happens to the muscle following a lack of dystrophin?
Myofiber degeneration Satellite cell activation Muscle regeneration Altered composition and stiffness of ECM
53
What are current treatments for DMD patients?
Corticosteroids Ventilation Cardiac care Psychological management Skeletal management
54
What are potential therapies for DMD?
Gene therapy through AAVs Readthrough of stop codons Antisense oligonucleotides Stem cells
55
How does gene therapy through AAVs alleviate DMD presentation?
They lessen the severity of the symptoms by changing the condition from DMD to Becker Since AAVs are not able to carry the whole gene The protein is too large
56
What is the main issue in treating MD?
It is a condition with multi-organ presentation Many aspects of MD need to be tackled
57
Which molecules are used in exon skipping?
Antisense oligonucleotides
58
Describe the process of exon skipping in DMD
Open reading frame disrupted in DMD forms truncated, non-functional dystrophin Exon responsible for the frameshift mutation is skipped This restores the reading frame Forms an internally deleted, partly functional dystrophin
59
What is the most common mutation that causes DMD?
Out-of-frame deletions Out-of-frame duplications Occurs to 70-75% of DMD patients
60
What is an outcome measure?
Indicates a measure of the result of a system relative to the aim Used as a measure of the success of a trial
61
What is normally the primary OM of a clinical trial?
Safety
62
Why are biochemical OMs of dystrophin patient not good measures of the improvement of a patient?
Tells you if the treatment increases dystrophin levels Does not necessarily correlate to the functional improvement of a patient
63
What type of OM is used to assess functional improvement?
Clinical OM 6 minute walk
64
Why is dystrophin quantification at protein and RNA levels difficult?
Low levels of a very large protein
65
What are ways to carry out biochemical OMs of treatment modalities used for DMD?
Can asses the exon skipping and dystrophin quantifications by immunohistochemistry and western blotting
66
What is a disadvantage of AONs?
Ineffectively target the heart 90% of DMD patients suffer cardiac complications
67
How can we increase the efficacy of AONs targeting the heart?
Conjugate AONs with cell penetrating peptides to enhance cell delivery
68
What is a disadvantage of using modified AONs?
Increased toxicity
69
What are targets of DMD therapy?
Premature stop codons Out of frame deletions or insertions Absence of functional dystrophin Loss of regenerative capacity Loss of muscle mass Disruption of signalling, inflammation and ROSs
70
What is a therapy that targets premature stop codons?
Aminoglucoside antibiotics Read through stop codons
71
What is a therapy that targets out of frame deletions or insertions?
Exon skipping with antisense oligonucleotides
72
What is a therapy that targets the absence of functional dystrophin?
Dystrophin gene therapy Utrophin upregulation
73
What is a therapy that targets the loss of regenerative capacity?
Stem cell therapy
74
What is a therapy that targets the loss of muscle mass?
Myostatin blockade
75
What is a therapy that targets that targets the disruption of signalling, inflammation and reactive oxygen species?
Pharmacological intervention
76
Examples of drugs used to aid the disrupted signalling, inflammation and ROSs seen in MD
Steroids Immunosuppressants Calcium buffering NF-kB blockade Anti-oxidants

Molecular Basis of Disease (28 decks)

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