Test 3 SCD & CF

Question 1

causation of SCD

Answer 1

Caused by a mis-sense mutation in the 6th codon of the beta chain of Hemoglobin

Question 2

What is the most common form of SCD?

Answer 2

Hb SS

Question 3

SCD: mutation

Answer 3

• glutamate converted into valine on the 6th codon
• Glu is hydrophilic
• Val is hydrophobic
• causes insoluble rod-like clumps

Question 4

SCD: what does the hydrophobic surface cause?

Answer 4

polymerization of deoxyhemoglobin

Question 5

consequences of SCD

Answer 5

• Pain crises
• Chronic pain
• Severe anemia
• Infections
• Spleen sequestration
• Gall stones
• Priapism
• Brain stroke
• Silent Brain injury
• Organ failure (including eyes & blindness)
• Acute Chest syndrome

Question 6

initial symptoms of SCD

Answer 6

• Dactylitis: swelling of hands & feet
• Fatigue, fussiness
• Yellowish skin (jaundice)
• Yellowish eyes (icteris)
• Shortness of breath

Question 7

diagnostic tests: SCD

Answer 7

• prenatal: test amniotic fluid or tissue from placenta
• newborn test: 5-40 day old
• filter paper test: clot = positive for SCD
• Gel Electrophoresis - HbA will run deeper in the gel b/c it’s more negative
• PCR & restriction enzyme digestion: look @ notes for visual sl19

Question 8

SCD therapy

Answer 8

• treat symptoms: pain, anemia, infections
• hydroxyurea increases fetal Hb (protects against HbS side effects)
• cure: myeloablative Hematopoietic Stem Cell Transplantation
• CRISPR/Cas 9: edit stem cell to have HbA gene and engraft in bone marrow
• Voxelotor: increases Hb’s affinity to O2

Question 9

CF: mutation

Answer 9

various mutations in the CFTR gene -> encodes a chloride ion channel that regulates salt and water movement in cells -> thick, sticky mucus and salty sweat

Question 10

most common CF mutation in US

Answer 10

3-base pair deletion ∆F508 or Phe508del -> loss of Phenylalanine at position 508 of the protein

Question 11

initial symptoms of CF

Answer 11

• salty skin
• baby doesn’t pass stool
• frequent coughing
• thick sputum / bloody
• abd discomfort / pain
• large, greasy stools
• poor weight gain and growth

Question 12

consequences of CF

Answer 12

• blocked airways -> trouble breathing
• mucus in airways -> infections
• Pneumothorax & bronchiectasis
• Blocked pancreas -> no digestive enzymes -> constipation, dehydration
• Salty sweat -> dehydration, increased heart rate, heat stroke, ↓ BP
• ↑ risk for diabetes
• osteoporosis, osteopenia, clubbing
• infertility
• respiratory failure

Question 13

diagnostic tests: CF

Answer 13

• newborn heel prick: genetic test and pancreatic function test
• sweat test: topical pilocarpine applied to skin, electrical current induces sweating, sweat collected, measure for Cl content, 30, 30-59, 60 mEq/L

Question 14

CF therapy

Answer 14

• antibiotics
• nebulizers
• bronchodilators
• chest physical therapy
• pancreatic enzyme
• vitamins
• increased fluid consumption
• Ivacaftor (Kalydeco®)
• Lumacaftor/Ivacaftor (Orkambi ®)

Question 15

Ivacaftor (Kalydeco®)

Answer 15

• CFTR conductance potentiator
• For patients > 6 yrs of age with select mutation G551D
• Improves lung function & increases weight
• Reduces exacerbations by 25-50%
• Oral administration – every 12 hrs

Question 16

Lumacaftor/Ivacaftor (Orkambi ®)

Answer 16

• potentiator (Ivacaftor): improves channel function
• corrector (Lumacaftor): improves processing and trafficking to surface of apical cell membrane
• For patients > 12 yrs of age with homozygous ∆F508
• Oral administration – every 12 hrs