Thalassemia and sickle cell disease

Question 1

Describe the composition of haemoglobin

Answer 1

1. 4 globin polypeptide chains
2. Haem is made in the liver, muscle and RBCs
3. Globin production localised to the RBC
4. Humans synthesise 6 different types of globin at different stages in life

Question 2

Haemoglobinopathies- Synthesis of an abnormal Hb structure (Qualititative)

What is it caused by?

Give examples

Answer 2

Point mutation that changes amino acid composition of protein

•E.g. HbS, HbC, HbD, HbE

Arise from mutations in HB genes and lead to reduced 0₂ carrying capacity

Question 3

Haemoglobinopathies- Reduced rate of synthesis of normal α or β globin chains (Quantitative)

What is this caused by?

Answer 3

Point mutation that changes amount of globin chain produced

•α and β Thalassaemias

Arise from mutations in HB genes and lead to reduced 0₂ carrying capacity

Question 4

Describe the geographical distribution of the thalassemia’s

Answer 4

Sickle cell- West Africa, Caribbean, East Mediterranean, middle east and South East Asia

Thalassaemia - Mediterranean, Middle east South East Asia, Southern Europe Southern China & Thailand

Question 5

Define Homozygous

Answer 5

•both genes carry mutation (e.g. SCD)

Question 6

Define Heterozygous

Answer 6

•only one gene carries mutation.

Question 7

Carriers =

Answer 7

Condition

Question 8

‘Trait’=

Answer 8

less severe

Question 9

What happens in alpha thalassaemia?

Answer 9

• Functioning HB must contain two alpha and two non-alpha like chains & rate of synthesis is equal
• In thalassemia we get an impaired synthesis of chains which leads to an excess of unpaired chains
• Produced on chromosome 16
• Are usually caused by α gene deletions, the number of deletions determines severity of disease
• Leads to defective foetal and adult HB
• Production of excess gamma chains which form tetramers known as HB Bart and an excess of β chains known as HB H
• Autosomal recessive disorder

Question 10

Show the genetics of alpha thalassemia

Answer 10

Question 11

What is Hb Bart syndrome?

Answer 11

• Bart’s hydrops fetalis is caused by deletion or inactivation of all four alpha-globin alleles leading to a severe deficiency in alpha-globin chains of Hb, and to the production of gamma-4 tetramers (Hb Bart’s) during fetal life, and beta-4 tetramers (HbH) postnatally.
• Hb Bart syndrome is characterized by hydrops fetalis, a condition in which excess fluid builds up in the body before birth. Additional signs and symptoms can include severe anemia, an enlarged liver and spleen (hepatosplenomegaly), heart defects, and abnormalities of the urinary system or genitalia.

Question 12

Alpha thalassaemia lab results

Answer 12

Question 13

How is alpha-Thalassaemia managed/treated?

Answer 13

Common Milder Form

•Occasional blood transfusion therapy•

Severe Cases

• Regular transfusions•Splenectomy• Iron chelation

*Iron overload should be monitored by serum ferritin levels and by liver magnetic resonance imaging (MRI).

Question 14

What is Beta-Thalassaemia?

Answer 14

• β –thalassaemia’s are a group of hereditary blood disorders
• 1 in 4 offspring if both parents are carriers of the Thalassaemia trait.
• Unlike α-thalassaemia, the majority of genetic lesions are point mutations rather than gene deletions

Question 15

Give examples of mutations that produce Beta thalassemia

Answer 15

Question 16

Show beta-thalassaemia classifications

Answer 16

β⁺thalassemia in which beta-globin protein is produced but at a reduced levelsn

β⁰thalassemia in which no beta-globin protein is produced

Question 17

What causes Beta-Thalassaemia major?

Answer 17

Two mutations both effecting β-globin synthesis.

alpha chain synthesis unaffected so leads to excess of alpha chains.These are unstable and precipitate out intoHeinz bodies in the cell

This interferes with RBC maturation and these cells will enter circulation with inclusions inside them; removed by the spleen§Excess of alpha chains will affect membrane lipid and protein composition causing rigid RBCs with shortened survival.