Skeletal Muscle & PNS Pathology

Question 1

Normal Muscle

Beehive is normal

Answer 1

Normal Muscle

Checkerboard is normal

• Grouping is abnormal ⇒ indicates denervation with reinnervation

Question 2

What are the pathologic reactions of muscle (3)?

Answer 2

• Hypertrophy
  
  • Occurs secondary to increased load due to exercise or pathologic condition
• Degeneration/necrosis
  
  • Destruction of all or part of a myofiber; stimulates infiltration by macrophages
• Regeneration
  
  • Satellite cells around degenerated fiber proliferate. Regenerating fiber has bluish color

Question 3

Describe denervation atrophy (neurogenic atrophy)

Answer 3

• Clusters of fibers (of one type) become smaller and develop angular contours (group atrophy)
• Lack of neural input results in:
  
  • Breakdown of myosin and actin
  • Resorptionof myofibrils
  • Decrease in cell size
• Both type 1 and type 2 fiber clusters are found

Question 4

Describe reinnervation:

Answer 4

• **Neighboring axons sprout and reinnervate denervated myocytes **
• Fiber assumes fiber type conferred by the neighboring axon
• This causes fiber type grouping

Question 5

Neurogenic vs. Myopathic

Answer 5

Neurogenic

• bimodal size distribution
• angulated fibers
• apparent increase in nuclei (nuclear clumps)
• no necrosis, regeneration, fibrosis, or inflammation

Myopathic

• random size variation
• round fibers
• centralization of nuclei
• necrosis, regeneration, +/-fibrosis, inflammation

Question 6

List the motor neuron diseases:

Answer 6

• Amyotrophic Lateral Sclerosis (ALS)
  
  • Aka Lou Gehrig’s disease
  • Motor Neuron Disease
• Spinal Muscular Atrophy (SMA)

Question 7

ALS

• Definition:
• Pathogenesis:
• Onset:

Answer 7

• Progressive, neurodegenerative d/o
• UMN + LMN degeneration;
  
  • normal sensation
• Onset: 50-60y of age (avg)

Question 8

What are the clinical s/s of ALS?

Answer 8

1. Weakness
   
   • Muscle atrophy of affected body part
   • Dysphagia, dysarthria
2. Fasciculations
   
   • Affected body part, tongue
3. Hyperreflexia
4. Positive Babinski
5. Spasticity
6. Pseudobulbar palsy
   
   • Emotional lability
7. Executive dysfunction

Question 9

Spinal Muscular Atrophy (SMA)

• Definition:
• Incidence:
• Demographics:
• Etiology:

Answer 9

• Degenerative LMN d/o of childhood>>adulthood
• 2nd most common autosomal recessive disorder
• Panethnic
• Homozygous deletion of exon 7 of SMN1 (survival motor neuron) gene

Question 10

What are the clincal s/s of SMA?

Answer 10

• Proximal muscle weakness >>> distal
• Dysphagia ⇒ GT
• Respiratory weakness ⇒ hypercapnia ⇒ death
  
  • Diaphragm failure
  • Intercostal weakness
• Normal intellect
• Areflexic on exam
• Different subtypes—infantile, older infant, childhood, adult onset

Question 11

Werdnig Hoffmann Disease

Answer 11

• Large groups of rounded atrophic fibers (panfascicular atrophy)
• Sparse scattered markedly hypertrophic fibers
• Differs from typical pattern of neurogenic atrophy seen in adults

Question 12

List the muscular dystrophies:

Answer 12

• X-linked muscular dystrophies
  
  • Duchenne MD (DMD)
  • Becker MD (BMD)
• Autosomal Muscular dystrophies
  
  • Myotonic MD (DM)

Question 13

Why is dystrophin important to the pathogenesis of muscular dystrophies?

Answer 13

• Mutation in Xp21
  
  • Deletion of ≥1 exons in DMD; duplications; stop codons
• LARGEST gene in humans
• Reason that 1/3rd of cases are new mutations
• Size of dystrophin does NOT matter as much as quantity of dystrophin does

Question 14

DMD vs BMD

Answer 14

• DMD ⇒ 99% have none/nearly no dystrophin
• BMD ⇒ 85% have abnormal dystrophin in reduced quantity
  
  • 15% have normal dystrophin in reduced quantity

Question 15

What are the clinical s/s of DMD?

Answer 15

1. Proximal muscle weakness
2. Intact milestones or slightly delayed
3. Gower’s maneuver
4. Face/Eyes SPARED
5. CK ↑↑↑ > 10,000
6. Slower movement than peers ⇒ wheelchair bound by 11-12y
7. Large calves
8. Waddling
9. Scapular winging
10. Contractures
11. Dilated cardiomyopathy
12. Intellectual impairment (average IQ 85)

Question 16

What is the clinical course of BMD?

Answer 16

• Later onset
• Near normal lifespan—mid 60’s
• Still have weakness

Question 17

Which lane represents DMD?

Answer 17

Lane 4: DuchenneMD: essentially no dystrophin protein present

Question 18

What is the most common muscular dystrophy in adults?

Answer 18

Myotonic dystrophy (DM)

Question 19

What is the etiology of DM?

Answer 19

• Autosomal dominant
• DM1 = dystrophia myotonica type 1
• CTG repeat expansion in DMPK gene on Ch 19
  
  • Normal 5-37 repeats
  • Full mutation is >80 repeats
• Genetic anticipation

Question 20

What is the major clinical sign in myotonic dystrophy?

Answer 20

Difficulty releasing grip ⇒ myotonia

• Impaired Cl^- conduction ⇒ slower repolarization ⇒ impaired relaxation
• Also will see foot drop

Question 21

What are other clinical s/s of DM?

Answer 21

• Weakness
  
  • Proximal muscles
  • Face—hatchet face
• Elongated face ⇒ “myopathic” face
• Temporal wasting
• Endocrine abnormalities
  
  • Testicular atrophy ⇒ balding
  • Diabetes (insulin resistance)
• Premature cataracts
• Cardiac arrhythmias—90% of pts
• ↓ Intelligence (higher repeat #)

Question 22

What are the metabolic myopathies (2)?

Answer 22

• Mitochondrial myopathies
  
  • Mutations in nuclear or mitochondrial DNA involved in oxid phosphorylation cause mito myopathies
• Glycogen storage diseases
  
  • Hereditary deficiency of enzyme involved in synthesis or degradation of glycogen

Question 23

What is MELAS and causes it?

Answer 23

• Mitochondrial myopathy, encephalopathy, lactic acidosis, & stroke-like episodes
• MtDNA mutation
  
  • Mutation codes for tRNA^(Leu)
  • Most common mutation m.3243A>G

Question 24

What are the 3 criteria for MELAS?

Answer 24

• Stroke-like episodes < 40y
  
  • Not vascular
  • Progressive cognitive impairment ⇒ dementia
• Encephalopathy
  
  • Seizures, stroke-like episodes
  • Neurodegenerative component
• Lactic acidosis, ragged-red fibers or both
  
  • Myopathy—proximal, eyes