Haemoglobinopathies

Question 1

What is the inheritance pattern for the majority of haemoglobinopathies?

Answer 1

Autosomal recessive

Question 2

Are alpha and beta globin genes on the same or different chromosomes?

Answer 2

Different.

Alpha: 16

Beta: 11

Question 3

What is the structure of Foetal Haemoglobin?

Answer 3

alpha2gamma2

Question 4

What are three different embryonic Haemoglobins?

Answer 4

ζ2ε2
ζ2γ2
α2ε2

Question 5

Name three broad types of haemoglobinopathies.

Answer 5

Alpha and beta Thalassaemias
Structural variants
Hereditary persistence of fetal haemoglobin (HPFH)

Question 6

What happens in alpha and beta thalassaemia?

Answer 6

Reduced synthesis of one or more globin chains.

Question 7

How many different structural variants are there in the haemoglobinopathies?

Answer 7

> 500 different variants.

Question 8

What is the effect of Hereditary persistence of foetal haemoglobin?

Answer 8

Nothing. It is clinically benign.

Question 9

What is the main cause of problems in the thalassaemias?

Answer 9

Relative imbalance between alpha and beta globin.

Question 10

What is the biggest physiological problem caused by thalassaemia?

Answer 10

Iron overload.

Question 11

How is iron overload caused in thalassaemia?

Answer 11

Abnormal erythroblasts die in the bone marrow causing release and breakdown of protein and therefore release of iron. There’s no effective mechanism for removing excess iron so it accumulates in organs leading to systemic overload.

Question 12

What gives the ‘hair on end’ appearance to the skull of someone with thalassaemia?

Answer 12

Thinning of skull, caused by increased erythropoiesis and expansion of the marrow.

Question 13

Why do people with thalassaemia often have to get splenectomies?

Answer 13

Because the hypochromic red cells that manage to get out of the bone marrow are destroyed in the spleen, which leads to splenomegaly.

Question 14

What mutation causes the majority of alpha-thalassaemias?

Answer 14

Large deletions

Question 15

What mutation causes the majority of beta-thalassaemias?

Answer 15

Point mutations.

Question 16

Which types of point mutations would result in degradation of the polypeptide produced by the beta-globin gene?

Answer 16

Nonsense and frames shift mutations

Question 17

What sort of mutation causes sickle-cell disease?

Answer 17

Point mutations

Question 18

What causes destruction of RBCs in Beta-thalassaemia (homozygous, also, incorrectly, called thalassaemia major)?

Answer 18

Produce only alpha globin chains, not beta, forming alpha4 globulin. These form aggregates, accumulate and precipitate in RBCs, causing damage.

Question 19

What type of anaemia is caused by beta-thalassaemia?

Answer 19

Haemolytic anaemia

Question 20

What effect does extramedullary erythropoiesis have on the liver and spleen?

Answer 20

Hepatomegaly

Splenomegaly

Question 21

What causes skeletal deformities in Beta-thalassaemia?

Answer 21

Anaemia -> Tissue anoxia -> Erythropoietin increase -> marrow expansion -> skeletal deformities

Question 22

Describe the red blood cells seen in Beta-thalassaemia.

Answer 22

Anisocytotic - irregular in size
Poikilocytotic - abnormal in shape
Microcytic (small)
Hypochromic (pale) RBCs

Question 23

What happens to other types of haemoglobin in homozygous beta-thalassaemia?

Answer 23

HbA2 is normal or moderately elevated

HbF is greatly elevated

Question 24

What does the treatment of beta-thalassaemia involve?

Answer 24

Blood transfusions every 3-4 weeks
Iron chelation therapy
Splenectomy
Hormone replacement therapy (women go through menopause at about 18years old)
Bone marrow transplant - cure (not everyone can do this though…)

Question 25

What is the phenotype of alpha-thalassaemia with only 2 functional genes?

Answer 25

Alpha-thalassaemia trait - mild anaemia.

Question 26

What is the phenotype of alpha-thalassaemia with only 1 functional gene?

Answer 26

HbH disease - mild to moderately severe anaemia.

Question 27

What is the phenotype of alpha-thalassaemia with no functional alpha-thalassaemia genes?

Answer 27

HbBart - hydrops fetalis, which is fatal before or around birth.

Question 28

What is the ‘South East Asian’ mutation for Alpha thalassaemia?

Answer 28

aa/–

Question 29

What is the ‘mediterranian’ mutation for alpha thalassaemia?

Answer 29

a-/a-

Question 30

What amino acid substitution is involved in sickle-cell anaemia?

Answer 30

Glu is substituted for Val

Question 31

Are all RBCs containing HbS tetramers sickled in shape?

Answer 31

No, red blood cells first become reversibly sickled When a biconcave erythrocyte becomes deoxygenated. After repeated cycles of deoxygenation, the erythrocyte becomes irreversibly sickled.

Question 32

What is the phenotype of Sickle Cell Disease (i.e. Homozygous, HbSS)

Answer 32

MCV/MCH may be normal or reduced

Hb significantly decreased. e.g. 60-80 g/L.

Question 33

What is the phenotype of Sickle cell train (i.e. Heterozygous, HbAS)

Answer 33

MCV/MCH may be normal or reduced.

Hb slightly or moderately reduced.

Question 34

What is an example of a double heterozygote?

Answer 34

e.g. a beta and alpha-globulin mutation. i.e. heterozygous for both.

Question 35

What is the aim of Gene therapy in Beta-thalassaemia?

Answer 35

Aim is to alter the imbalance of alpha and beta chains by using RNAi (interfering RNA) to reduce alpha-globin mRNA.

Question 36

How could epigenetic modifications be used as a gene therapy for the treatment of thalassaemia and sickle cell disease?

Answer 36

Small molecules could be used to induce HbF.