BB Lecture 10: Disorders of Skeletal Muscle (VC only Dr. Bonneman)

Question 1

Somite

Answer 1

The embroyological precursor to muscles; divides into dermamyotome (muscles of back; epaxial) and sclerotome (hypaxial muscles; limbs/body wall)

Question 2

Sarcolemma

Answer 2

a thin membrane enclosing a striated muscle fiber

Question 3

Floppy baby

Answer 3

Can be due to any point of the axon pathway…CNS, spinal cord, motor axon, NMJ, sensory axon and even connective tissue

Question 4

Sarcoplasmic reticulum

Answer 4

the calcium storage and release organelle of muscle

Question 5

dystrophin protein

Answer 5

located in the cytoplasm of a muscle fiber

Question 6

muscle striation

Answer 6

form of fibers that have repeating sarcomeres

Question 7

Congenital myopathies

Answer 7

-Different from muscular dystrophies because there is no active muscle breakdown and ongoing regeneration
-may show clinical improvement or a relatively stable course
-characterized by diagnostically important microscopic and ultrastructural features upon examination of the muscle biopsy
Example: Nemaline myopathy

Question 8

Nemaline Myopathy

Answer 8

-Disease of thin filaments
-Characterized by the nemaline rods that appear in histological slides under electron microscope
Nema = thread
-nebulin and actin are the two most commonly mutated genes
Primary example of a congenital myopathy

Question 9

Muscular Dystrophy

Answer 9

MOA: deletion in dystrophin gene
Characterized by
-degeneration
-regeneration
-connective and fatty tissue infiltration
Muscular dystrophy is NOT specific diagnosis because they there are many types of disorders that cause these symptoms

Question 10

Duchenne Muscular Dystrophy

Answer 10

MOA: caused by mutation in dystrophin gene so you have defective dystrophin protein
Onset is 2-4 years so NOT FLOPPY BABY

Question 11

Gower’s Maneuver

Answer 11

• demonstrates proximal muscle weakness

- seen in DMD but NOT specific for DMD

Question 12

Trendelenburg Sign

Answer 12

excessive hip swing due to proximal muscle weakness, brought out by climbing stairs

• seen in DMD but NOT specific for DMD
• weakness in gluteus medius

Question 13

Becker Muscular Dystrophy

Answer 13

• like muscular dystrophy in that cardiomyopathy is an important complication in patient
• also due to dystrophin gene

Question 14

IQ in Duchenne dystrophy

Answer 14

-people’s IQ are shifted to the left (less IQ)

MOA: brain isoform in dystrophin

Question 15

Dystrophin Gene

Answer 15

• one gene, many products

- largest locus in humans

Question 16

DMD in female carriers; Lyonization

Answer 16

When one X is repressed in expression vs. the other
Hinders expression of normal OR mutated gene
-in cases of DMD in females, lyonization induces DMD because of inactivation of one normal copy

Question 17

Creatine Kinase (CK) levels

Answer 17

indication of muscle breakdown…higher CK = more breakdown

Question 18

Symptoms of DMD

Answer 18

Symptoms:

• proximal progressive weakness
• “pseudo”hypertrophy
• elevated Creatine Kinase (mark of muscle breakdown)
• Gowers and Trendelenburg

Complications:

• cardiomyopathy
• respiratory insufficiency
• scoliosis

Question 19

Symtom of Becker Muscular dystrophy (BMD)

Answer 19

• onset is variable, wheelchair is older than 15 y.o
• CK elevated
• milder form of DMD

Question 20

Sarcoglycanopathies

Answer 20

-autosomal recessive DMD and BMD-like muscular dystrophies
-limb-girdle muscular dystrophies
-dystrophin is normal but the sarcoglycan complex is reduced
Part of “dystrophin associated protein complex

Question 21

Facioscapulohumeral Dystrophy (FSHD)

Answer 21

• loss of material in chromosome 4
• if you lose all of the last end of the chromosome you don’t have disease
• but if you have just some of the end of the chromosome left, you have disease
• you only get disease if you have deletion in A telomere and NOT in B telomere

Why?
-A telomere has a polyadenylation site on there
-as you lose material, you transcribe DUX4 and bad shit happens
DUX4 is a transcription factor

• larger the deletion earlier the onset/more sever the disease
• 3rd most common dystrophy after Duchenne and myotonic dystrophy

Question 22

DUX4

Answer 22

Transcription factor involved in FSHD etiology

Question 23

Exon 51

Answer 23

converts DMD to BMD

-treatment for DMD

Question 24

Recombinant adeno-associated virus (rAAV)

Answer 24

Delivery of dystrophin that will result in BMD

Question 25

Myopathy vs. Dystrophy

Answer 25

Dystrophy are degenerative, regenerative and have connective and fatty tissue infiltration AND is a subset of myopathies
Myopathies in general do not have to be degenerative

Question 26

Symptoms of facioscapulohumeral Dystrophy (FSHD)

Answer 26

• weakness in face
  
  • scapula
  • biceps
  • distal leg