Hemoglobinopathies

Question 0

How many copies of alpha and beta genes are normal?

Answer 0

Two alpha

One beta

Question 1

What is the normal tetrameric composition of hemoglobin and what are homotetramers?

Answer 1

Normal composition is 2 alpha and 2 beta subunits

Homotetramers are 4 alpha, 4 beta, or 4 gamma subunits (all insoluble)

Question 2

What subunits is fetal hemoglobin comprised of?

Answer 2

2 alpha

2 gamma

Question 3

At birth, what two forms of hemoglobin switch in proportion, and what are their subunits?

Answer 3

HbF (2 alpha, 2 gamma) & HbA (2 alpha, 2 beta)

Question 4

Three types of genetic disorders of hemoglobin

Answer 4

Structural (qualitative) - normal synthesis, altered globin property
Thalassemias (quantitative) - low or zero synthesis of one globin chain
Defective globin switching - hereditary persistence of fetal hemoglobin

Question 5

What type of genetic disorder is sickle cell anemia?

Answer 5

A structural or qualitative disorder

Beta-S globin has 20% solubility of normal globin.

Question 6

What type of disorder is hemoglobin C disease?

Answer 6

Structural or qualitative disorder
Beta-C
Occurs at same codon as sickle cell, but causes different AA and phenotype.

Question 7

How is sickle cell anemia diagnosed?

Answer 7

Southern Blot test
Beta-S mutation changes sequence at a restriction site, disallowing cutting by restriction enzyme
Southern Blot test will reveal one band
Same test can reveal multiple alleles (HbA, HbC, HbS)

Question 8

Causes and consequences of Hb-Kempsey

Answer 8

High O2 affinity in heme due to permanent relaxed state
Low O2 delivery to cells
Results in Polycythemia

Question 9

Causes and consequences of Hb-Kansas

Answer 9

Lower O2 affinity
Less O2 in RBC
Leads to cyanosis

Question 10

Two types of thalassemias, their causes, and when they affect individuals.

Answer 10

Alpha Thalassemia (B4, G4)
Low or zero alpha globin, excess beta globin precipitates
Both fetal and post natal effects
Deletion of alpha globin gene(s)

Beta Thalassemia (A4)
Low or zero beta globin, excess alpha globin precipitates
Post natal defects only (beta not active in fetal blood)
Caused by point mutations in Beta gene
Sometimes by deletions in LCR or beta gene cluster

Question 11

What is the alpha-thalassemia 1 trait and where is it predominant?

Answer 11

aa/–
Causes mild thalassemia
Predominantly in Southeast Asia

Question 12

What is the alpha-thalassemia 2 trait and where is it predominant?

Answer 12

a-/a-
Mild thalassemia
Predominantly in Africa

Question 13

What do the alpha-thalassemia genotypes a-/– and –/– result in, respectively?

Answer 13

a-/– results in severe anemia

–/– results in fetal death (HbF is 2 alpha, 2 gamma)

Question 14

What is hydrops fetalis?

Answer 14

The condition of –/– alpha-thalassemia

Question 15

What is HbH disease?

Answer 15

Results from a-/– genotype

Question 16

What is the a-thal 1 allele?

Answer 16

(–)

Found in Southeast Asia

Question 17

What is the a-thal 2 allele?

Answer 17

(a-)

Found in Africa, Mediterranean, and other Asia

Question 18

How are beta-thalassemias observed throughout development?

Answer 18

Hemoglobin is normal during fetal development (2a, 2g)

Alpha Homotetramers occur after birth (no beta = A4)

Question 19

2 general categories of beta-thalassemias

Answer 19

Thalassemia major and Thalassemia minor

Question 20

What are the genotypes of Beta-thalassemia minor?

Answer 20

B0-heterozygote: one good beta allele, one absent allele

B+-heterozygote: one good beta allele, one partially effective allele

Question 21

What are the genotypes of beta-thalassemia major?

Answer 21

B0-thalassemia: zero good beta alleles

B+-thalassemia: one partially effective allele

Question 22

What are complex beta-thalassemias caused by?

Answer 22

Large deletions