Muscular Dystrophy

Question 1

The M line anchors ________ and the Z disc anchors _________.

Answer 1

M line: myosin

Z disc: actin

Question 2

What is the fundamental thing that Becker and Duchenne muscular dystrophies share?

Answer 2

They both arise from dystrophin mutations.

They are both dystrophinopathies

Question 3

How would you very quickly describe Duchenne MD?

Answer 3

Inherited, progressive neuromuscular disease.

X-linked recessive.

Question 4

What is the most common form of MD?

Answer 4

Duchenne

Question 5

What is the frequency of DMD in the male population?

Answer 5

1/3500 males

Question 6

What is the prognosis for DMD?

Answer 6

Variable progression but typically palliative by age 20-25.

Question 7

DMD appears at about age _____, but ________

Answer 7

2-3 years onset,

4-5 years for diagnosis (more time for muscles to develop and healthy milestones to be missed).

Question 8

The gene for dystrophin is located at _____

Answer 8

Xp21.2

Question 9

What’s the first thing noticed on onset with DMD?

Answer 9

Weakness in the calves

Question 10

How big is the dystrophin gene?

Answer 10

Massive - 2.5Mbp, 79 axons.

Question 11

What’s F-actin?

Answer 11

Just the filamentous form of actin. Not complicated.

Question 12

Without proper anchoring of dystrophin to DAPC, what’s the problem?

Answer 12

The contractions create acute (transient) sarcolemma ruptures, which allow for Ca2+ influx.

Question 13

What MD pathophysiological problem is related to signalling?

Answer 13

DAPC has a signalling role; when it’s disrupted, muscle fibres fail to regenerate. This is an important to the progressive aspect of the disease.

Question 14

What is a biochemical blood marker for DMD and where does it come from?

Answer 14

Creatine Kinase - leaks out of the cell like calcium leaks in.

Question 15

What is creatine kinase for?

Answer 15

Catalyses the formation of phosphocreatine - an energy store for muscles.

Question 16

Why is it called calf PSEUDOhypertrophy?

Answer 16

Because the muscle tissue isn’t getting bigger - the size comes from infiltrations of fat and fibrotic tissue into the muscle.

Question 17

What’s something apart from calcium fuckery that leads to necrosis?

Answer 17

Inflammatory response to the cell rupture.

Question 18

What external physical symptom is the CLASSIC sign of DMD?

Answer 18

GOWER’S MANEUVER

Question 19

As a short answer prompt: break down for me the three aspects of DMD diagnosis.

Answer 19

1. Physical Examination
2. Lab Diagnostic Techniques
3. Family history

Question 20

As a short answer prompt, break down the lab diagnostic techniques:

Answer 20

1. Blood screening
2. Gene testing
3. Muscle biopsy

Question 21

List the three major physical signs.

Answer 21

1. GOWER’S MANEUVER
2. Trendelenberg gait
3. Missing physical/intellectual milestones (inc. late walking, toe walking, frequent falls, speech/difficulty hearing).

Question 22

Which is the term for inability to stabilise the pelvis, resulting in a dropping away from the load-bearing leg and a leaning toward the load-bearing side to correct balance?

Answer 22

Trendelenburg Gait

Question 23

Which is the term for a rolling into the prone position, widening of the base and “climbing up” the body to rise from a supine position?

Answer 23

Gower’s sign.

Question 24

List four physical milestones and another buzzword for physical examinations that can tie them all together.

Answer 24

Pull-to-sit (not head lag)
Unsupported sitting/self-sitting
Gait
Running

Refer to the MOTOR DELAY ALGORITHM for advancement to lab testing (CK blood test).

Question 25

What needs to test positive before genetic testing or a muscle biopsy?

Answer 25

Creatine kinase positive in the blood test.

Question 26

Why might you check creatine kinase if there's no family history?

Answer 26

Because he's not walking or there's Gower's sign.

Question 27

Gower's sign is such a hallmark that they'll go to a CK test even if.....

Answer 27

.... even if there's no family history.

Question 28

If there's a family history they'll check CK if .....

Answer 28

...... if there's pretty much any suspicion of abnormal muscle development.

Question 29

If we don't know family history we might check CK if ...

Answer 29

.... there's abnormal blood transaminases (AST, ALT), which are part of routine blood tests.

Question 30

Quickly, list three types of genetic DMD testing.

Answer 30

1. multiplex PCR 2. quantitative assay 3. next-gen sequencing.

Question 31

If you see someone's 3yo kid doing the Gower sign and falls over a lot, what would I tell them in my capacity as an omniscient med sci undergrad?

Answer 31

Don't say their kid's got DMD. You'll sound like an idiot to the doctor they go to. Tell them not to fret until they have DNA testing results because DMD is a common thing to diagnose based on phys exam alone.

Question 32

What does a healthy dystrophin-stained biopsy look like?

Answer 32

Nice, tiled, thin layers of connective tissue, relatively even size

Question 33

What does a Becker's MD slide look like compared to a DMD slide?

Answer 33

Beckers: relatively fucked DMD: basically absent dystrophin.

Question 34

What is gonadal mosaicism and why is it significant to screening algorithms?

Answer 34

Gonadal mosaicism refers to mutations in germline cells (not somatic cells), which are the cause of around 20% of all diagnosed cases. So just because the mother and father tested double-negative doesn't mean the offspring can't inherit muscular dystrophy.

Question 35

What is a manifest carrier?

Answer 35

There's this thing called LYONISATION which is where X chromosomes are non-ramdomly inactivated (presumably to stop overdosing on X genes). If this happens to a carrier, she can manifest symptoms of DMD.

Question 36

How common are manifest carriers?

Answer 36

About 5% of female carriers; | About 2/3 of carriers have elevated CK.

Question 37

What's the only pharmacological treatment of DMD and what's it's down side? What are they also often given?

Answer 37

Corticosteroids (e.g. prednisone) but the side effects are pretty significant and require constant monitoring. They'll often get NSAIDs too.

Question 38

List 3 non-drug treatments for DMD.

Answer 38

Surgery Physiotherapy & excercise Diet & nutrition

Question 39

What do we hope to achieve with current available treatments?

Answer 39

We basically can only hope to control the symptoms and the progression of muscle degeneration.

Question 40

Short answer prompt: What's the relevance of genetic counselling? (three headings)

Answer 40

1. X-linked recessive 2. Gonadal mosaicism 3. Manifest carriers (lyonisation)

Question 41

In what circumstances can DMD usually be diagnosed in the presymptomatic stage?

Answer 41

Family history or increased CK (NB the kid can't walk yet)

Question 42

A negative result for CK is a negative result for DMD. True or false?

Answer 42

True.

Question 43

The NH2 terminus of dystrophin attaches to ________ and the COOH terminus attaches to DAPC.

Answer 43

Amino: F-actin. Carboxy: DAPC.

Question 44

65% of DMD mutations are...... | 5-15% are...

Answer 44

large intragenic deletions | large intragenic duplications

Question 45

There are 8 experimental approaches. What are they?

Answer 45

``` Antisense oligonucleotides Aminoglycoside antibiotics (exon skipping) Stem cell therapy Myoblast transfusion Gene correction Gene addition Proteosome inhibition Upregulation therapy (utrophin) ```

Question 46

What's the idea of antisense oligonucleotides?

Answer 46

An antisense mRNA strand binds to the mutated region of an affected dystrophin immature mRNA, which modifies the exon phasing of the pre-mRNA and thus the exon content of the final gene. The result is still a defective dystrophin gene but MUCH MORE function retained than whatever fuckery was being caused by the original mutation, with an improved prognosis.