Disorders of Skeletal Muscle

Question 1

Embryo review: What mesodermal structures give rise to skin, muscle, and bone? What are some signaling molecules that act on them to differentiate the cells?

Answer 1

Somites. Wnt, Shh, BMPs… all that.

Question 2

What’s delamination in the context of limb muscle development?

Answer 2

When undifferentiated cells of myotome leave and migrate into the growing limb. This uses genes. :P

Question 3

What is the most mechanically stressed part of muscle?

Answer 3

The sarcolemma - specifically the interface between the muscle cell plasma membrane and the basement membrane.

Question 4

What does a “floppy” baby actually mean? Is it more likely to be (non-dystrophy) myopathy or muscular dystrophy?

Answer 4

Floppy = hypotonic (muscles don’t resist passive movement, may or may not be accompanied by loss of strength). More likely to be myopathy, as dystrophies have later onsets.

Question 5

Name the 6 parts of the “neuraxis” to which you could localize a myopathy.

Answer 5

Brain (cortex and cerebellum), spinal cord, anterior horn cell, peripheral nerves, NMJ, muscle (and tendons/connective tissue)

Question 6

What’s the difference between a (congenital) myopathy and a dystrophy?

Answer 6

Distrophy is caused by aberrant breakdown and degeneration of muscle. Myopathy has no active breakdown, though the muscle is not fully functional.

Question 7

Name the 4 “classical” congenital myopathies. Is each caused by a defect in one gene?

Answer 7

Nemaline myopathy
Centronuclear/myotubular myopathy
Central core disease
Multi/minicore myopaty
No, each one is genetically heterogeneous.

Question 8

Name histologic features of nemaline myopathy

Answer 8

Red staining inclusions (in a modified Gomori Trichrome stain) in the muscle fibers.

Question 9

What would you see in electron microscopy of nemaline myopathy?

Answer 9

Areas of big black threads between normal sarcomeres: “nemaline rods”

Question 10

What does “nema-“ mean? Relevance?

Answer 10

thread. Thread-like nemaline rods appear in EM of muscle biopsy of nemaline myopathy.

Question 11

Nemaline myopathy is a disorder of what structures? What are some specific proteins involved (name 4-5ish).

Answer 11

Thin filaments. Nubulin, actin, tropomyosin 2 & 3, Troponin T, Cofilin-2

Question 12

What is the mode of inheritance of nemaline myopathy?

Answer 12

Autosomal dominant or recessive: it depends on the gene responsible. Some, such as in actin, can be dominant-negative. Others are inherited recessively.

Question 13

Why do myopathies and dystrophies often cause scoliosis?

Answer 13

Muscles on one side of back are weaker.

Question 14

What are 3 thing’s you’ll see in muscular dystrophy histology?

Answer 14

Degeneration, regeneration (with hypertrophy) and infiltration with connective and fatty tissue.

Question 15

Why are muscles bigger (pseudohypertrophy) in MD? (2 things)

Answer 15

Hypertrophy of intact muscle fibers.

Infiltration with fatty and connective tissue

Question 16

What’s a histologic feature of regenerating cells? Where does it come from?

Answer 16

Nucleus in center of muscle cell. These come from satellite cells.

Question 17

What’s the most common MD?

Answer 17

Duchenne MD. X-linked recessive.

Question 18

What enzyme can you detect in the blood in Duchenne MD? Why is it there?

Answer 18

Creatine Kinase. Release when degenerating myocytes break open.

Question 19

What are 3 major complications of Duchenne MD? Which one can we do least about?

Answer 19

Cardiomyopathy, respiratory insufficiency, scoliosis. Can support the latter two, but can’t do much about the cardiomyopathy.

Question 20

3 clinical features of Duchenne MD?

Answer 20

Progressive proximal weakness, pseudohypertrophy, elevated Creatine Kinase (CK)

Question 21

What’s the Gower’s Maneuver?

Answer 21

From lying on back, child can’t sit up and stand. Rather turns over, braces self with hands, and walks legs up to stand.

Question 22

How might Duchenne MD be seen in gait?

Answer 22

Trendelberg sign: hip abductor weakness -> excessive hip swinging to compensate for drop (epecially when walking up stairs)

Question 23

What’s a more mild form of MD than Duchenne? Clinical signs? Major complication?

Answer 23

Becker MD. Weak muscles, calf pseuohypertrophy, high CK. Still can have cardiomyopathy.

Question 24

Why might the dystrophin gene be so susceptible to mutation?

Answer 24

It’s really big.

Question 25

Is IQ affected by Duchenne MD? Practical implication?

Answer 25

Yes, the bell curve is shifted to the left. If you see mental retardation, you may want to consider Duchenne MD.

Question 26

What does Dystrophin do?

Answer 26

Anchors a complex (dystrophin-associated proteins) that attaches myocyte plasma membrane to connective tissue.

Question 27

What are revertant fibers in Duchenne MD? Why do they revert?

Answer 27

Fibers in MD patients that express dystrophin. Second mutation removes exon with frameshift - restoring functionality of protein.

Question 28

What does staining for Dystrophin look like in a female carrier for Duchenne MD?

Answer 28

A small number of myocyte membranes will lack Dystrophin, due to lyonization. (can in rare cases cause significant myopathy)

Question 29

What does dystrophin staining of myocytes look like in a patient with Becker MD?

Answer 29

present on all cells, but “irregular”

Question 30

What’s the difference in genetic cause between Becker and Duchenne MD? Significance?

Answer 30

Becker is an in-frame deletion, Duchenne’s causes a frameshift. Becker MD is less severe because there is still protein present (it’s just less functional / unstable).

Question 31

What experimental Tx for Duchenne MD takes advantage of knowledge about revertant fibers?

Answer 31

Using an oligonucleotide to force exon-skipping, keeping the mRNA in-frame.

Question 32

Mutations in genes other than Dystrophin can cause muscular dystrophy. What do these genes have in common? What was one specific example mentioned and its mode of inheritance?

Answer 32

They’re part of the ‘dystrophin-associated protein complex.” Sarcoglycan ->limb girdle MD, autosomal recessive. (I don’t think you need to know this)