Hemoglobinopathies

Question 1

What chromosome is alpha globin gene on?

Answer 1

Chromosome 16

Question 2

What chromosome is the beta globin & Epsilon gene on?

Answer 2

Chromosome 11

Question 3

Key points: What is alpha globin?

Answer 3

ɑ globin is the primary ɑ-like chain at all stages.

Question 4

Key points: What is ϒ globin?

Answer 4

ϒ globin is the primary β-like globin in fetal development in HbF

Question 5

Key points: What is β globin prdominant and what type of hemoglobin?

Answer 5

Not until ~6 months postpartum in HbA

Question 6

Key points: What is δ globin? What hemoglobin?

Answer 6

δ globin is a minor adult β -like globin chain (HbA2)

Question 7

Pathophysiology of the thalassemias (4 steps and lead to 3 things)

Answer 7

1. Decreased synthesis of either alpha or beta globin
2. Imbalance of alpha and beta subunits
3. Damage to erythrocyte precursors (red blood cells unhealthy)
4. Ineffective erythropoiesis and hemolysis cells are more fragile and break down)

Leads to anemia, extramedullary hematopoiesis, and increased intestinal iron absorption.

Question 8

How does absence of Beta globin genes impact development?

Answer 8

Absence of functional β globin genes in survivable in fetal life because of ϒ chain production.

Question 9

Nomenclature: Silent carrier ɑ thalassemia

Answer 9

ɑ - / ɑ ɑ

Question 10

Nomenclature: ɑ thal trait

Answer 10

ɑɑ/- - or ɑ - / ɑ -

Question 11

Nomenclature: ɑ Thalassemia Intermedia

Answer 11

ɑ - / - - (HbH Disease)

Question 12

Nomenclature: ɑ Thalassemia Major

Answer 12

ɑ - / - -

Question 13

Nomenclature: β Thalassemia Trait

Answer 13

β / β+ or β / β0

Question 14

Nomenclature: β Thalassemia Intermedia

Answer 14

β+/β+ or β+/β0

Question 15

Nomenclature: β Thalassemia Major

Answer 15

β+/β0 or β0 / β0 or βE/β0

Question 16

Primary genetic cause for Alpha Thal

Answer 16

Deletional Mutation

Question 17

What disease is - - / - - ?

Answer 17

Hemoglobin Bart’s hydrops fetalis

Question 18

Beta-thalassemia most common genetic mutation. What is the rarer type of mutation?

Answer 18

Common: Point mutations affecting gene expression.

Rare: Deletions affecting the beta globin locus or the entire LCR

Question 19

What do blood cells look like on thalassemia blood smears? What is this feature a sign of?

Answer 19

Nucleated blood cells, and a sign of bone marrow stress.

Question 20

What are complications from thalassemia?

Answer 20

• Growth failure
• Hepatosplenomegaly due to extra medullary erythropoiesis

Question 21

How does iron overload occur?

Answer 21

Results from transfusions and from increased GI absorption of iron

Question 22

Target organs from iron overload, and what happens to them?

Answer 22

• Liver: Cirrhosis
• Heart: Cardiomyopathy, conduction abnormalities
• Pancreas: Diabetes
• Pituitary: Growth failure, other hormonal disturbances.

Question 23

Thalassemia treatments

Answer 23

• Transfusion as needed
• Iron chelation to eliminate excess iron
• Bone marrow transplantation
• Luscpartercept (TGFbeta signaling inhibitor)
• Gene therapy

Question 24

What is sickle cell disease caused by?

Answer 24

Caused by homozygosity for βs or compound heterozygosity of βs with other variants

Question 25

What does increased oxygen affinity look like?

Answer 25

• Increased oxygen loading in lungs
• Decreased oxygen off-loading in tissues
• Compensatory erythrocytosis

Question 26

What does decreased oxygen affinity look like?

Answer 26

• Usually adequate oxygen loading in lungs
• Increased oxygen off-loading in tissues
• Compensatory decrease in erythropoiesis
• Occassionally peripheral cyanosis due to deoxygenated hemoglobin

Question 27

What are unstable hemoglobins?

Answer 27

Hemoglobins with unstable alpha or beta globin chains

Question 28

What is methemoglobinemia?

Answer 28

Globin mutations making hemoglobin prone to reduction of iron from ferrous (Fe2+) to ferric (Fe3+) state

Question 29

Whats wrong with Methemoglobin?

Answer 29

Cannot carry oxygen

Question 30

How is methemoglobin commonly caused?

Answer 30

Due to mutations in cytochrome b5 reductase or to exposures to drugs or toxins