Sickle Cell Anemia & Thalassemia

Question 1

What is the genetic defect that causes sickle cell anemia?

What is teh major symptom that impacts QOL for sickle cell pts?

Answer 1

Homozygous SS in the B-globin gene (HBB)

–> The 6th aa is mutated from glutamic acid to valine

PAIN due vasoocclusive crises

Question 2

Why does changing the 6th amino acid, Glu to Val, cause sickle cell?

Answer 2

Glutamic acid is charged; Val is uncharged

Puts HbS in its deoxy form, which has a hydrophobic patch that causes the Hb molecules to aggregate into strands and insoluble fibers –> sickle shape, stiffer, fragile

Question 3

Treatments for sickle cell

Answer 3

• Pain mgmt, antibiotics, blood transfusions, bone marrow transplants
• Hydroxyurea alters the maturation of erythroid precursors and promotes expression of fetal Hb (HbF)
  
  • At high enough expression of HbF, it will become incorporated into the HbS strands, but won’t bind the next HbS –> HbS can’t polymerize –> shorter HbS strands are less likely to form fibers!

Question 4

What conditions can promote a sickle cell crisis?

Answer 4

Conditions that promote the deoxy form: exercise or hypoxic conditions (e.g. high altitudes)

Question 5

What are the two types of alpha globin genes? Which is expressed early in embryonic development and which is the main one during fetal development and throughout life?

both expressed from within a ___

Answer 5

zeta(ς): expressed early in embryonic development

alpha: expressed throughout life and fetal development as the main a-lgobin

Both expressed within a clustered locus control region

Question 6

the B-globin genes are also exprssed form within a clustered LCR. Describe the 4 types

Answer 6

• B is the major allele; found in adult Hb (HbA)
• Delta is a second type of adult Hb (HbA2)
• y is exprssed in fetal development and found in fetal Hb (HbF)
• Epsilon is expressed in the embryonic yolk sac; with the zeta chain, it makes the embryonic Hb (HbE)

Question 7

1. In the first few weeks of embryonic development ___ predominates as the major Hb and is expressed in the yolk sac.
2. By week 9, HbE is replaced by ___, and a small amt of __. ​​​
3. At birth, there is a switch to ___, although ~5% comes from either __ or __

Answer 7

In the first few weeks of embryonic development HbE predominates as the major Hb and is expressed in the yolk sac.

By week 9, HbE is replaced by HbF, and a small amt of HbA.

At birth, there is a switch to HbA, although ~5% comes from either HbA2 or HbF

Question 8

Hereditary persistance of fetal hemoglobin (HPFH) is caused by a mutation that inhibits genetic switch from __globin to __globin afater birth.

What’s its clinical relevance?

Answer 8

inhibits y to B-globin switch after birth

Benign, but co-inheritance of HPFH in pts that have some B-chain mutations involved in Sickle cell and B Thalassemia can actually alleviate clinical symptoms.

_{Thus, researchers are trying to reproduce the HPFH mutation in promoters of genes for the y chain in progenitor cells from SCD donors –> produce RBCs with increased HbF sufficient to reduce HbS polymerization}

Question 9

What is methemoglobinemia?

Answer 9

The oxidation of Fe²⁺ to Fe³⁺ –> methemoglobin (metHb). Binding of O₂ to methemoglobin result sin increased affinity of O₂ to the 3 other heme sites (still ferrous) –> can’t release the O₂ to tissue

Blue skin, shortness of breath, anxiety, headache

Question 10

Causes of methemoglobinemia

Answer 10

Caused by

• Certain chemicals and reactive oxygen intermediates
  
  • ​Nitrate, some antibiotics, some anesthetics
• Autosomal dominant mutations in Hb that lead to mroe rapid oxidation of heme
• Deficiencies in NADH-cytochrome B5 reductase/diaphorase I, which normally reduces met-Hb back to Hb
  
  • This rxn also needs NADH, so a deficiency in pyruvate kinase

Question 11

Tx of methemoglobinemia

Answer 11

Intravenous infusion of methylene blue reduces Fe3+ back to Fe2+

Question 12

Thalassemia

Answer 12

Autosomal recessive deletion or point mutation that diminishes or eliminates the production of 1 of the two hemoglobin chains –> anemia

Reduction in oxygen delivery to the tissues reduces the E that can be derived from food

Question 13

Difference between alpha and beta thalassemia

Answer 13

B-thalassemia: mutations in the B-globin gene cluster; high incidence in Mediterranean populations

a-thalassemia: mutations in the a-globin gene cluster; high incidence in Southeast Asian, Middle East, and African populations

^{Both persist bc they provide some resistance to malaria}

Question 14

Where do mutations in thalassemia occur?

Answer 14

Coding regions or regulatory regions

Question 15

B^o-thalassemia / B-thalassemia Major / Cooley’s Anemia

Answer 15

• Complete absence of B-globin expression due to mutants in both copies of the B-globin gene
• Symptoms
  
  • Severe anemia in the first year of life
  • Iron buildup in the heart and other organs –> heart failure in 2nd or 3rd decade of life

Question 16

B-Thalassemia MInor

Answer 16

Heterozygous mutation in the B-globin gene –> 50% reduction of expression from the B-globin locus

Little to no symptoms

Question 17

B⁺-thalassemia

Answer 17

Mutations in the control regions (LCR or immediate upstream promoter) –> reduced expression of B-globin –> anemia

Ex) Deletions obliterate the enhancer sequences in the LCR needed for transcription

Question 18

a-Thalassemia Major / a-Thalassemia ^(-)

Answer 18

Like B^o-thalassemia, there is NO a-globin expressed –> still births

Question 19

Hemoglobin H disease

Answer 19

a-globin expression is 25% of normal and the excess B-globin chains form unstable hemoglobin H (HbH)

–> less effective O₂ delivery; severe microcytic anemia

Question 20

a-Thalassemia minor

Answer 20

50% reduction of a-globin

–> mild microcytic anemia

Question 21

What is the inheritance pattern of sickle cell and why has it persisted?

Answer 21

Autosomal recessive

Enhanced resistance to malaria

Question 22

Benzocaine, sulfonamide, dapsone, nitrates, and other chemicals that have oxidizing activity can cause

Answer 22

methemoglobinemia

Question 23

Why are B-thalassemias usually not detected until 1-12 months after birth

Answer 23

They aren’t evidence until synthesis of the y chain of hemoglobin has diminished

Question 24

What is the B-globin locus control region?

Answer 24

A region fo DNA found 6-22 kb upstream of the first globin gene; enhances expression of beta globin chains, which need to be synthesized in very large numbers