Sickle Cell And Thalassemia

Question 1

Sickle cell anemia (general)

Answer 1

AR

Defect in the beta-globin gene (HBB)

Must be homozygous to present

Symptoms:

• fatigue
• paleness
• shortness of breath
• jaundice (due to chronic and rapid breakdown of erythrocytes)

Question 2

Structure of sickle cell anemia (HbS)

Answer 2

Defect lies in the 6th amino acid in the beta-globin chain

Glutamic acid —> valine

Nonconservative amino acid change…

From a charged molecule —> non-charged

Alters the electrophoretic mobility of the protein

Question 3

Hemoglobin C disease

Answer 3

Same amino acid 6 that is changed in sickle cell

But instead —> Lysine

Milder amino acid subsitution…generally does not need therapy

Question 4

Structural changes the glu—>val mutation causes in the sickle cell anemia

Answer 4

Promotes self-assembly of HbS into strands

Strands can also align and crystalize into fibers

Promoted when HbS is in the deoxy form

Therefore sickle cell crisis can be caused by conditions that promote the deoxy form like exercise, high altitudes

These altered higher order structure alters the shape of RBCs…RBCs become stiffer and less flexible

Do not flow easily through narrow capillaries

Question 5

Treatment of sickle cell anemia

Answer 5

Pain management

Blood transfusions, iron overloading is a side effect

Prophylactic antibiotics are used to prevent infections

Bone marrow transplants for stroke patients, recurrent acute chest syndrome and chronic pain patients

Hydroxyurea = drug

Question 6

Hydroxyurea drug

Answer 6

Used to treat sickle cell anemia

Alters maturation of erythroid precursors and indirectly promotes the expression of HbF

HbF can replace the abnormal HbS

Generating shorter HbS strands that are less likely to form fibers…since HbF will be incorporated into the strands and cannot add more HbS once that happens

Question 7

Types of alpha-globin genes

Answer 7

Alpha = main one during fetal development and throughout life

Zeta = very early in embryonic development and is made in the yolk sac

Question 8

Types of beta-globin genes

Answer 8

Beta = major allele, found in adult Hb

Gamma = during fetal development and found in HbF

Delta = expressed in a second type of adult Hb (HbA2)

Epsilon = embryonic yolk sac = embryonic Hb with zeta alpha chains

Question 9

HbA

Answer 9

Adult Hb

Alpha2beta2 (>95%)

Question 10

HbA2

Answer 10

Second type of adult Hb

Alpha2delta2

Question 11

HbF

Answer 11

Fetal Hb

Alpha2gamma2

Question 12

HbE

Answer 12

Embryonic Hb

Zeta2epsilon2

Question 13

Timelines for the types of Hb

Answer 13

First few weeks of embryonic development = HbE

Week 9 = HbF

Birth -> death = HbA

Question 14

Mutations in the alpha and beta chains in HbA

That can enhance formation of metHb

Answer 14

Mutations are AD

Enzyme that is relevant = NADH-cytochrome B reductase

Normally reduces metHb back to Hb

Question 15

NADH deficiencies and methemoglobinemia

Answer 15

NADH supplies reducing power for the reaction that reduced metHb —> Hb

Genetic deficiencies to enzymes that would reduce levels of NADH (like pyruvate kinase) —> can also cause methemoglobinemia

Question 16

Treatment of methemoglobinemia

Answer 16

Patients = chocolate colored blood and blue tint to their mucous membranes

Related to hypoxia and can include anxiety, headache and shortness of breath

IV infusion of methylene blue = can reduce Fe3+ back to Fe2+

Question 17

Thalassemia

Answer 17

One of the most common single gene defects

Mutation, either deletion or point, that diminishes or eliminates the production of 1 of the 2 chains of Hb

Causes anemia and reduces the blood’s ability to carry O2

AR mutations

Question 18

Beta-thalassemia vs. alpha

Answer 18

Mutations occur in the beta cluster genes

Mediterranean populations

Or alpha cluster…SE asia, ME, and africa

Question 19

Alpha vs beta genes clusters

Answer 19

Alpha = chromosome 16

Beta = chromosome 11

Regulated by the Locus Control Region (LCR)

Thalassemia can be caused by mutations within the regulatory regions as well as the coding regions

Mutations can occur

• intron/exon junctions = blocking correct mRNA splicing
• missense mutations in an exon may cause a premature stop codon
• frameshift insertion/deletion may generate an altered coding of amino acids

Question 20

Beta(o) - thalassemia

Answer 20

Mutants in both copies of beta globin gene

Ineffective erythropoiesis…and these patients present in the 1st year of life with severe microcytic hypochomic anemia

Buildup of iron in heart and other organs results in heart failure as early as the 2nd or 3rd decade

Question 21

Beta(-) thalassemia

Answer 21

Only one allele is affected

Little to no symptoms

If mutation is more severe = beta thalassemia intermedia

Question 22

Beta (+) thalassemia

Answer 22

Mutations in the control regions (LCR or the immediate upstream promoter region)

Deletions obliterate the enhancer sequences in the LCR…needed for high level transcription

—> reduced expression of beta-globin —> can cause anemia

SO an issue with expression levels…not mutated form

Question 23

Alpha(-)-thalassemia

Answer 23

Essentially no alpha globin expressed (analogous to beta(o) thalassemia)

Results in still borns