Sickle Cell Anemia & Thalassemia Flashcards
What is the genetic defect that causes sickle cell anemia?
What is teh major symptom that impacts QOL for sickle cell pts?
Homozygous SS in the B-globin gene (HBB)
–> The 6th aa is mutated from glutamic acid to valine
PAIN due vasoocclusive crises
Why does changing the 6th amino acid, Glu to Val, cause sickle cell?
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
Treatments for sickle cell
- Pain mgmt, antibiotics, blood transfusions, bone marrow transplants
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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!
What conditions can promote a sickle cell crisis?
Conditions that promote the deoxy form: exercise or hypoxic conditions (e.g. high altitudes)
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 ___
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
the B-globin genes are also exprssed form within a clustered LCR. Describe the 4 types
- 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)
- In the first few weeks of embryonic development ___ predominates as the major Hb and is expressed in the yolk sac.
- By week 9, HbE is replaced by ___, and a small amt of __.
- At birth, there is a switch to ___, although ~5% comes from either __ or __
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
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?
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
What is methemoglobinemia?
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
Causes of methemoglobinemia
Caused by
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Certain chemicals and reactive oxygen intermediates
- Nitrate, some antibiotics, some anesthetics
- Autosomal dominant mutations in Hb that lead to mroe rapid oxidation of heme
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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
Tx of methemoglobinemia
Intravenous infusion of methylene blue reduces Fe3+ back to Fe2+
Thalassemia
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
Difference between alpha and beta thalassemia
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
Where do mutations in thalassemia occur?
Coding regions or regulatory regions
Bo-thalassemia / B-thalassemia Major / Cooley’s Anemia
- 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
B-Thalassemia MInor
Heterozygous mutation in the B-globin gene –> 50% reduction of expression from the B-globin locus
Little to no symptoms
B+-thalassemia
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
a-Thalassemia Major / a-Thalassemia (-)
Like Bo-thalassemia, there is NO a-globin expressed –> still births
Hemoglobin H disease
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
a-Thalassemia minor
50% reduction of a-globin
–> mild microcytic anemia
What is the inheritance pattern of sickle cell and why has it persisted?
Autosomal recessive
Enhanced resistance to malaria
Benzocaine, sulfonamide, dapsone, nitrates, and other chemicals that have oxidizing activity can cause
methemoglobinemia
Why are B-thalassemias usually not detected until 1-12 months after birth
They aren’t evidence until synthesis of the y chain of hemoglobin has diminished
What is the B-globin locus control region?
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
