Haemoglobinopathies

Question 1

Describe the structure of adult haemoglobin (Hb A)

Answer 1

There are 4 global subunits (two alpha and two beta) which an iron-containing haem group

Question 2

Describe the alpha globin gene cluster for haemoglobin

Answer 2

On chromosome 16 there are two genes that code for the alpha subunit of haemoglobin (Therefore there are 4 copies in total, 2 maternal and 2 paternal) but there is also a zeta gene that can produce the zeta subunit instead of the alpha subunit

Question 3

Describe the beta globin gene cluster for haemoglobin

Answer 3

On chromosome 11 there is a gene that codes for the beta globin chain, but also the epsilon gene, delta gene and two gamma genes that can produce these subunits instead of the beta subunit

Question 4

Where is the gene for the zeta globin subunit found?

Answer 4

Chromosome 16

Question 5

Where is the gene for the alpha globin subunit found?

Answer 5

Two copies on chromosome 16

Question 6

What is the structure of haemoglobin Gower 1 (embryonic haemoglobin)?

Answer 6

Consist of two zeta and two epsilon subunits

Question 7

What is the advantage of Hb Gower 1 in the first stages of embryonic development?

Answer 7

It has a very high affinity for oxygen which allows greater uptake from the placenta

Question 8

Where is embryonic haemoglobin (Hb Gower 1) produced?

Answer 8

Embryonic yolk sac until about 6 weeks gestation

Question 9

What is the structure of foetal haemoglobin (Hb F)?

Answer 9

There are two alpha subunits and two gamma subunits

Question 10

Where is foetal haemoglobin (Hb F) produced?

Answer 10

Spleen and liver

Question 11

What is the advantage of haemoglobin F for the foetus?

Answer 11

It has a greater affinity for oxygen than maternal haemoglobin which allows it to take up oxygen from placental blood

Question 12

What is the structure of adult haemoglobin (Hb A)?

Answer 12

Two alpha and two beta subunits

Question 13

What is the structure of adult haemoglobin 2 (Hb A2)?

Answer 13

Two delta subunits and two alpha subunits

Question 14

What is meant by thalassaemia?

Answer 14

A condition that is caused by inadequate quantities of one or other of the subunits that make up adult haemoglobin

Question 15

What is alpha thalassaemia?

Answer 15

This occurs when one or more of the alpha genes on chromosome 16 are defective or faulty

Question 16

What is beta thalassaemia?

Answer 16

This occurs when there is a point mutation on chromosome 11 which interferes with beta subunit production by varying amounts

Question 17

What does the severity of alpha thalassaemia depend on?

Answer 17

The number of gene allies that are defective or missing

Question 18

What are the four kinds of alpha thalassaemia?

Answer 18

> Alpha thalassaemia minima (1 defective gene)
Alpha thalassaemia minor (2 defective genes)
Haemoglobin H disease (3 defective genes)
Hydrops fetalis/alpha thalassaemia major (4 defective genes)

Question 19

Describe alpha thalassaemia minima

Answer 19

This is where there is a defect in one alpha gene on chromosome 16, as there are 3 other functional genes this has minimal effect on Hb synthesis so there are no clinical symptoms (may have a slightly lower MCV)

Question 20

Describe alpha thalassaemia minor

Answer 20

There is a defect in two alpha genes on chromosome 16 but there are still 2 functional genes left, therefore there is normal RBC production, but they may have mild microcytic hypo chromic anaemia

Question 21

Describe haemoglobin H disease

Answer 21

This is where there is a defect in 3 alpha genes on chromosome 16 and this causes the production of two unstable haemoglobin’s into the blood: haemoglobin parts (has 4 gamma subunits) and haemoglobin H (has 4 beta subunits) which have a higher oxygen affinity than normal so least to poor oxygen release in tissues. There is microcytic, hypochromic anaemia in these individuals.

Question 22

What is the structure of haemoglobin Barts?

Answer 22

Has four gamma subunits and is unstable

Question 23

What is the structure of haemoglobin H?

Answer 23

Has four beta subunits and is unstable

Question 24

Describe hydrops fetalis (alpha thalassaemia major)

Answer 24

They have little circulating haemoglobin, and that they do have is haemoglobin Barts; this leads the infant to be oedematous and this condition is incompatible with life so the foetus cannot live outside of the uterus and may not survive gestation, if it does it will die shortly after birth.

Question 25

Describe the genetic inheritance of beta thalassaemia

Answer 25

Beta thalassaemia is an autosomal recessive condition. Those who are heterozygous are said to have beta thalassaemia trait (or beta thalassaemia minor), whereas those with homozygous recessive beta genes have beta thalassaemia major

Question 26

How does beta thalassaemia lead to hypochromic microcytic anaemia?

Answer 26

Due to the reduced synthesis of beta globin subunits, excess alpha globin subunits are produced in the developing erythroblasts in the bone marrow, and the alpha tetramers formed are unstable and subsequently precipitate out onto the erythrocyte membrane. This precipitation leads to intra-medullary destruction of the developing erythroblasts which ultimately leads to erythroid hyperplasia and ineffective erythropoiesis.

Question 27

What are the complications of untreated beta thalassaemia major?

Answer 27

Hypochromic, microcytic anaemia, bone marrow expansion, splenomegaly, bone deformity, failure to thrive from 6 months of age (when there is a switch from foetal haemoglobin), heart failure and death by age 3-4

Question 28

What would blood tests for those who are carriers for beta thalassaemia indicate?

Answer 28

``` > Reduced Hb levels > Very low MCV (microcytic) > Very low MCH > Normal Hb A > Elevated Hb A2 > Normal Hb F ```

Question 29

What would blood tests for those with beta thalassaemia major display?

Answer 29

``` > Very low Hb levels > Very low MCV (microcytic) > Very low MCH > Very low/absent Hb A > Elevated Hb A2 > Elevated Hb F ```

Question 30

How is thalassaemia major treated (both alpha and beta)?

Answer 30

Regular transfusions (with iron chelators to reduce iron-overload), splenectomy, allogeneic bone marrow transplant

Question 31

What is the problem with administering regular blood transfusions in the treatment of thalassaemia major?

Answer 31

It can lead to iron overload as these individual's aren't iron deficient and the blood will contain more iron

Question 32

What is sickle cell disease?

Answer 32

This disease involves a mutant form of one of the beta subunits which causes the red cells to become 'sickle shaped'

Question 33

What are the complications of sickle ell disease?

Answer 33

Sickle cells can obstruct capillaries and restrict blood flow to an organ which leads to ischaemia, pain and end-organ damage

Question 34

What are the clinical signs of sickle cell disease?

Answer 34

Haemolytic anaemia, microvascular occlusion and large vessel damage

Question 35

Explain the pathophysiology of sickle cell disease

Answer 35

There is a single amino acid substitution in the beta gene on chromosome 11 (GAG --> GTG) which leads to valine being presented instead of glutamic acid . This causes the production of beta chain S (haemoglobin S)

Question 36

How does sickle cell disease cause anaemia?

Answer 36

The haemoglobin S has a decreased survival time so there is less haemoglobin circulating at any one time, and this causes anaemia

Question 37

What are the potential consequences of sickle cell disease?

Answer 37

Anaemia, increased susceptibility to infection, vaso-occlusive crises and chronic tissue damage due to occlusion and ischaemia.

Question 38

How is sickle cell disease managed?

Answer 38

Infection prophylaxis, analgesia for painful crises, transfusions if there are complications, bone marrow transplantation and hydroxyurea prescription to treat painful crises

Question 39

Why may hydroxyurea be given to manage sickle cell disease?

Answer 39

It can increase Hb F production which may reduce a painful crises

Question 40

What type of screening is there for sickle cell disease?

Answer 40

Carrier screening in areas with a history and/or neonatal screening using a heel-prick or cord blood test

Question 41

What is haemoglobin C?

Answer 41

This is a autosomal recessive disorder where there is mutation in the beta gene leading to the production of HbC. If an individual is homozygous with the mutation, nearly all Hb is in the Hb C form --> mild haemolytic anaemia. If the individual is heterozygous they have 1/3 of Hb C in their circulation which doesn't cause anaemia.

Question 42

What are the consequences of haemoglobin C?

Answer 42

Haemoglobin C is a mutation in which there is an abnormal beta subunit. This causes reduced plasticity and flexibility of the erythrocytes. This causes excess red cell destruction (haemolysis) which can cause anaemia.

Question 43

What is haemoglobin E?

Answer 43

Haemoglobin E (HbE) is an abnormal hemoglobin with a single point mutation in the β chain. Haemoglobin and it's inheritance is autosomal recessive.

Question 44

What are the consequences of haemoglobin E?

Answer 44

Mild beta thalassaemia develops at around 6 months after birth when Hb F stops being available.