PBL 9 - Thalassaemia

Question 1

How does the subunit structure of normal adult haemoglobin differ from that of fetal haemoglobin? (2 marks)

Answer 1

Normal adult haemoglobin consists of two alpha (1/2 mark) and two beta (1/2 mark) subunits (chains) . Fetal haemoglobin consists of two alpha (1/2 mark) and two gamma subunits (1/2 mark).

Question 2

What abnormality occurs specifically in alpha thalassaemia? (1 mark). What are the different degrees of this disease, and describe briefly the signs corresponding to each degree of severity. (2 marks)

Answer 2

In Alpha thalassaemia there is reduced synthesis (1/2 mark) of the alpha subunits of haemoglobin (1/2 mark).

There are usually four copies of the gene to produce alpha chain haemoglobin (1/2 mark). If all four copies are missing this is incompatible with life and leads to in-utero death (1/2 mark). Three copies missing leads to severe microcytic anaemia (1/2 mark). Loss of one or two genes does not normally lead to any symptoms (1/2 mark).

Question 3

What is the main abnormality that would be detected in a blood test from patients with beta thalassaemia major (1 mark)

Answer 3

Microcytic anaemia

Question 4

4. What is the major form of haemoglobin in patients with beta thalassaemia major (1 mark)

Answer 4

Fetal Haemoglobin (HbF)

Question 5

5. Explain briefly why Kadeer Ahmed has a protruberant abdomen (1 mark)

Answer 5

There is enlargement of the liver and spleen (1/2 mark) as a result of excessive red cell destruction (1/2 mark) and extramedullary haemopoiesis (1/2 mark) (any two half marks)

Question 6

Name two main forms of treatment suitable for Kadeer (2 marks)

Answer 6

Regular blood transfusions (1/2 mark) with iron chelation to prevent iron overload (1/2 mark)
Bone marrow transplant (1 mark)

Question 7

Where is blood cell production in the fetus, newborn and adult? (3)

Answer 7

o Before birth:
= Mesoblastic stage - At 3rd week: Yolk sac +mesothelial layers of the placenta (HbGower1)
=Hepatic stage - At 6 weeks – Liver & Spleen (HbF)
=Myeloid stage- 3rd month onwards - the bone marrow
o After birth:
=Age up to 5 years : The bone marrow in all bones (HbA)
= Age 5 to 20-25 years : Marrow of the long bones
= Age 25+ years: marrow of the membranous bones

Question 8

What is the difference between the structure of embryonic and fetal hb? (2)

Answer 8

Fetal Hb - HbF - A2Y2

fetal - Hb Gower 1 - Z2E2

Question 9

What is the percentage of HbA, HbF and HbA2 in adult blood?

Answer 9

o HbA – 10% in neonates, 96-97% in adults
o HbA2 - <1% in neonates, 2-2.5% in adults
o HbF – 90% in neonates, <1% in adults

Question 10

What chromosome do B thalassaemia mutations occur on? (1)

Answer 10

e within the gene complex

itself or in promoter or enhancer regions on chromosome 11.

Question 11

What are the two genotypes of B thalassaemia ? (2)

Answer 11

heterozygous beta thalassaemia trait (minor) and

homozygous beta thalassaemia (thalassaemia major or intermedia).

Question 12

Why are iron chelators given and give an example? (1)

Answer 12

E.g Desferioxamine
bind to iron in blood
Prevents the Fenton reaction occurring (hydroxyl radicals form) which can cause cirrhosis, growth retardation, heart failure, diabetes

Question 13

Why might genetic counselling be necessary, what would they need to discuss? (1)

Answer 13

• Pregnant woman with Hb abnormality – test partner
• Both have abnormality – risk of defect in offspring

Discuss - foetus affect, termination offered

Question 14

How can prenatal diagnosis of thalassaemia be done? (1)

Answer 14

DNA (chorionic villous or amniotic fluid) or fetal blood

Question 15

Normal structure and function of haemoglobin

Answer 15

4 polypeptide chains with a haem group

Each haem has 1 atom of ferrous iron that combines with 4x oxygen

Question 16

What chromosome is the gene for alpha globin on

Answer 16

Ch 16

4x genes for alpha + zeta

Question 17

What chromosome is the gene for beta globin on

Answer 17

Ch 11

5x genes for beta

Question 18

Structure of embryonic, fetus, adult hb

Answer 18

Embryonic Hb - Hb Gower 1 – Z2E2
• Fetus Hb – HbF – A2Y2
• Adult Hb – HbA – A2B2 and HbA2 – A2D2

Question 19

When do babies switch to adult hb

Answer 19

3-6 months after birth

the gamma is replaced by beta

Question 20

What is thalassaemia

Answer 20

Reduction or absence globin chain production

Question 21

Alpha thalassaemia

Answer 21

Deletion on one or more alpha genes on ch 16

Question 22

What are the different types of alpha thalassaemia

Answer 22

Alpha thalassaemia minima
Alpha thalassaemia minor
Haemoglobin H
Alpha thalassaemia major

Question 23

What is alpha thalassaemia minima

Answer 23

One alpha gene defective
Asymptomatic as 3 alpha globin chains are enough
Silent carriers

Question 24

What is alpha thalassaemia minor

Answer 24

Two alpha genes defective

Mild microcytic hypochromatic anaemia

Question 25

Haemoglobin H

Answer 25

3 alpha genes defective
2 unstable haemoglobins present in the blood - Hb Barts and Hb H
Severe microcytic hypochromatic anaemia
Higher affinity for oxygen- poor release in tissues

Question 26

What is hb barts and hb H

Answer 26

Hb Barts - G4

Gb H - B4

Question 27

Alpha thalassaemia major

Answer 27

4 alpha genes defective
Foetus cannot live outside of uterus (stillborn)
Hb that is present is all hb barts

Question 28

What sort of inheritance is beta thalassaemia

Answer 28

Autosomal recessive

Question 29

What is beta thalassaemia

Answer 29

point mutation on genes on ch 11 in hb b gene

Question 30

When does beta thalassaemia manifest

Answer 30

When switch from gamma to beta chain after birth

Question 31

Beta thalassaemia minor

Answer 31

Heterozygous - carrier state

Asymptomatic

Question 32

Beta thalassaemia intermedia

Answer 32

Moderate anaemia

Still can make some beta chains

Question 33

Beta thalassaemia major

Answer 33

Lack of beta haemoglobin
Severe microcytic anaemia
Cooley’s

Question 34

Signs and symptoms of B thalassaemia

Answer 34

 Bone deformities – extramedullary haematopoiesis
 Jaundice due to haemolytic anaemia
 Abdominal distention due to hepatosplenomegaly
 Failure to thrive from 6 months of age
 Heart failure and death by age 3-4

Question 35

What would you see in investigations of B thalassaemia

Answer 35

 Full blood count – Microcytic anaemia, reticulocytosis
 Haemoglobin electrophoresis – HbA very reduced or absent, HbA2 slightly increases, HbF increased
 Blood film – Hypochromatic, microcytic rbc and reticulocytes present
 Other tests – Increased bilirubin, increased lactate dehydrogenase
 Difference between hetero and homozygote is that homozygote will have very reduced/absent HbA, increased HbF and very reduced Hb

Question 36

How do you treat beta thalassaemia

Answer 36

1) Blood transfusions 2-4 per week
2) + Iron chelators e.g desferioxamine preventing fenton reaction
3) Allogenic bone marrow transplant
4) Splenectomy

Question 37

Why jaundice in scenario

Answer 37

Raised serum bilirubin and LDH due to increased ineffective erythropoiesis and haemolysis, bilirubin is a breakdown product of haemoglobin and LDH is released from damaged erythroblasts and red cells

Question 38

Why was the liver and spleen enlarged

Answer 38

excessive red cell destruction and extramedullary haemopoiesis

Question 39

Function of 2,3 DPG

Answer 39

When O2 starts to be unloaded from oxyhaemoglobin the beta chains separate permitting entry of the metabolite 2,3-diphosphoglycerate (2,3-DPG) this in turn reduces the affinity of the whole molecule for O2. This entry of 2,3 DPG is responsible for the sigmoid form of the haemoglobin O2 dissociation curve. The normal position of the curve depends on the concentration of 2,3-DPG, H+ ions and CO2 in the red cell and on the structure of the haemoglobin molecule