BB Lecture 10: Disorders of Skeletal Muscle (VC only Dr. Bonneman) Flashcards
Somite
The embroyological precursor to muscles; divides into dermamyotome (muscles of back; epaxial) and sclerotome (hypaxial muscles; limbs/body wall)
Sarcolemma
a thin membrane enclosing a striated muscle fiber
Floppy baby
Can be due to any point of the axon pathway…CNS, spinal cord, motor axon, NMJ, sensory axon and even connective tissue
Sarcoplasmic reticulum
the calcium storage and release organelle of muscle
dystrophin protein
located in the cytoplasm of a muscle fiber
muscle striation
form of fibers that have repeating sarcomeres
Congenital myopathies
-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
Nemaline Myopathy
-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
Muscular Dystrophy
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
Duchenne Muscular Dystrophy
MOA: caused by mutation in dystrophin gene so you have defective dystrophin protein
Onset is 2-4 years so NOT FLOPPY BABY
Gower’s Maneuver
- demonstrates proximal muscle weakness
- seen in DMD but NOT specific for DMD
Trendelenburg Sign
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
Becker Muscular Dystrophy
- like muscular dystrophy in that cardiomyopathy is an important complication in patient
- also due to dystrophin gene
IQ in Duchenne dystrophy
-people’s IQ are shifted to the left (less IQ)
MOA: brain isoform in dystrophin
Dystrophin Gene
- one gene, many products
- largest locus in humans
DMD in female carriers; Lyonization
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
Creatine Kinase (CK) levels
indication of muscle breakdown…higher CK = more breakdown
Symptoms of DMD
Symptoms:
- proximal progressive weakness
- “pseudo”hypertrophy
- elevated Creatine Kinase (mark of muscle breakdown)
- Gowers and Trendelenburg
Complications:
- cardiomyopathy
- respiratory insufficiency
- scoliosis
Symtom of Becker Muscular dystrophy (BMD)
- onset is variable, wheelchair is older than 15 y.o
- CK elevated
- milder form of DMD
Sarcoglycanopathies
-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
Facioscapulohumeral Dystrophy (FSHD)
- 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
DUX4
Transcription factor involved in FSHD etiology
Exon 51
converts DMD to BMD
-treatment for DMD
Recombinant adeno-associated virus (rAAV)
Delivery of dystrophin that will result in BMD
Myopathy vs. Dystrophy
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
Symptoms of facioscapulohumeral Dystrophy (FSHD)
- weakness in face
- scapula
- biceps
- distal leg
