Genetics

Question 1

• Duchenne Muscular Dystrophy is what kind of disorder?
• Due to what kind of mutation in which gene?

Answer 1

MOST COMMON

• X-linked disorder
• Due to frameshift or nonsense mutations
  
  • lead to truncated dystrophin protein (no functional protein)
    
    • inhibited muscle regeneration

DMD is the largest protein coding human gene; increase risk of spontaneous mutations

Question 2

• What is the function of dystrophin ?
  
  • Loss of dystrophin results in (like in Duchenne MS)?

Answer 2

• Function:
  
  • The Dystrophin protein provides a structural link between the muscle cytoskeleton and extracellular matrix to maintain muscle integrity.

Loss of dystrophin results in:

• myonecrosis
• increase creatine kinase and aldolase are seen

Question 3

How is diagnosis of Duchenne Muscular Dystrophy confirmed?

Answer 3

• Western blot
• muscle biopsy

Question 4

• What are some physical symptoms of Duchenne Muscular Dystrophy ?
  
  • When does onset of symptoms appear?

Answer 4

• Onset before age of 5
• Symptoms:
  
  • Weakness begins in pelvic girlde muscles (wheelchair)
    
    • progresses superiorly
  • Psudeohypertrophy of calf muscle
    
    • due to fibrofatty replacement of muscle
  • Gower manuever
    
    • use upper extremities to help stand up
  • Waddling gait

Question 5

Histology of Duchenne Muscular Dystrophy?

Answer 5

Fibrofatty replacement of muscle

Question 6

• Becker MD is what kind of disorder?
  
  • due to a mutation?
• Compare severity of Duchenne MD

Answer 6

• X linked disorder
• Due to:
  
  • non-frameshift mutation
    
    • partially functional instead of truncated
• Less severe than Duchenne

Question 7

• When do onset of symptoms begin in Becker MD?
  
  • How is it diagnosed?

Answer 7

• Symptoms show up later; adolescent or early adulthood
  
  • progressive disorder
• Diagnosed when:
  
  • patient shows pattern of weakness
  • first problem in hips, thighs and shoulders
  • Pseudohypertrophy

Question 8

• Difference between Becker and Duchenne MD?
  
  • Variation between Becker?

Answer 8

• Becker vs. Duchenne
  
  • slower onset and progression
    
    • except cardiac muscle
• Becker vs. Becker
  
  • due to variation in site of mutation

Question 9

• Myotonic Dystrophy is the second most common?
  
  • What aret he two types?
• Shows signs of?

Answer 9

• Second most common disorder
  
  • Show signs of anticipation
• Type 1 and Type 2:
  
  • Type 1 more common
  • Both repeat expansion disorders

Question 10

• When do symptoms of Myotonic Dystrophy begin?
  
  • What is seen?

Answer 10

• Symptoms begin in adults
  
  • less severe
• Show signs of:
  
  • weakness with progressive muscle wasting
  • prolonged muscular contractions
    
    • can’t relax certain muscles
  • speech may slur, jaw may lock

Question 11

• Compare Type 1 vs. Type 2 Myotonic Dystrophy:
  
  • gene encoded

Answer 11

• Type 1: (autosomal dominant)
  
  • DMPK gene, protein kinase
  • CTG repeat
    
    • more repeats = more severe = earlier onset (anticipation)
• Type 2:
  
  • CNBP gene, transcription factor
  • CCTG repeat

Question 12

• What symptoms are seen in Myotonic Dystrophy Type 1?
  
  • Due to mutation in?
• My Tonia, My Testicles, My Toupee, My Ticker

Answer 12

• CTG repeat expansion in DMPK gene
  
  • abnormal expression of myotonin protein kinase
• Symptoms:
  
  • myotonia (inability to relax voluntary muscle)
  • muscle wasting
  • cataracts
  • testicular atrophy (My Testicle)
  • frontal balding (My Toupee)
  • arrhythmia (My Ticker)

Question 13

• Pompe Disease (Type II) is due to which deficient enzyme?
  
  • results in accumulation of?
• What is test is helpful in identifying?

Answer 13

• Defect in:
  
  • Lysosomal alpha 1,4 glucosidase (acid maltase)
    
    • important in glycogen degradation
• Results in:
  
  • glycogen accumulates in lysosomes
  • distorts myotubes and weakens muscles
• Identify with:
  
  • Periodic acid-Schiff stain
    
    • identifies glycogen

Question 14

• Symptoms of Pompe Disease?
  
  • “Pompe trashes the pump”
• Onset?

Answer 14

• Progressive weakness
  
  • respiratory muscles, hips, thighs, shoulders
• Cardiac problems
• Liver problems

Onset is infantile to adults

• earlier onset = faster progression

Question 15

• Charcot-Marie-Tooth disease are also known as?
  
  • Group of progressive hereditary nerve disorders relatived to defective?
• Inheritance pattern?

Answer 15

• also known as hereditary motor and sensory neuropathy (HMSN)
• Due to:
  
  • defective production of proteins involved in structure and function of peripheral nerves or myelin sheath
    
    • all problems stem from lack of stimulation
• Inheritance pattern:
  
  • autosomal dominance

Question 16

• Charcot-Marie-Tooth disease (HMSN) is associated with what symptoms?

Answer 16

• Associated with:
  
  • foot deformities (pes cavus)
    
    • weak muscles opposed by strong ones distort normal position
  • lower extremity weakness
    
    • muscles atrophy due to lack of use
  • sensory deficits
    
    • dymelination of nerves leads to weakness, atrophy and chane in sensation

Question 17

• Ataxia (loss of control of body movement) disorders share what 4 symptoms?

Answer 17

1. unsteady gait
2. fine motor skill disturbance
3. slurred speech
4. disturbance of eye movement

Question 18

• Friedreich ataxia is due to?
  
  • results in?
• Inheritance pattern?

Answer 18

• Due to:
  
  • GAA repeat on chrom. 9
    
    • in gene that encodes frataxin (iron binding protein)
• Results in:
  
  • impairement in mitochondrial function
    
    • degeneration of multiple spinal cord tracts
      
      • muscles weakness and loss of DTRs, vibratory sense and propioception
• Inheritance:
  
  • autosomal recessive

Question 19

• When is onset/ what does it present with at first?
  
  • What are later symptoms of Friedrich’s ataxia?

“Friedreich is Fratastic: he’s your favorite frat brother, always staggering and falling but has a sweet, big heart.

Answer 19

Loss of function of frataxin

• Onset:
  
  • in childhood with kyphoscoliosis
• Findings: (starts slowly)
  
  • Staggering gait
  • Frequent falling
  • pes cavus
  • diabetes mellitus
  • hypertrophic cardiomyopathy

Question 20

• Ataxia-telangiectasia is a defect in which gene?
  
  • causes?
• Inheritance pattern?
• Presents with what signs?

Answer 20

• Defect in:
  
  • ATM gene
    
    • failure to repair DNA ds breaks = cell cycle arrest
      
      • makes them sensitive to ionizing radiation
• Inheritance
  
  • autosomal recessive
• Signs:
  
  • Triad
    
    • cerebellar defects (ataxia)
    • Spider Angiomas (telangiectasia- spider veins)
    • IgA deficiency
      
      • increase risk of infection

Question 21

• Amyotrophic (no-muscle-nourishment) lateral sclerosis (ALS) is due to?
  
  • results in?
• Sporatic vs. familial?

Answer 21

• Due to:
  
  • progressive degeneration of upper and lower motor neurons (loss of cortical and spinal cord motor neurons)
    
    • can be caused by defect in superoxide dismutase 1
• Result in:
  
  • atrophic and spastic paralysis
  • asymmetric limb weakness
  • bowel/bladder deficits
• Onset:
  
  • usually seen after 50 (sporatic)
  • 10% have familial forms

Question 22

Differences between Becker, Duchenne and Limb Girdle Dystrophy:

• Inheritance
• Distribution
• Gene/Locus
• Key Concept

Answer 22