Haemaglobinopathies

Question 1

Recall the structure of Hb

Answer 1

It is a tetramer made up of usually 2 alpha and 2 beta globin chains with a haem group (comprised of Fe2+ and prophyrin)

Question 2

Recall the 3 main forms of Hb and the differences in golbin chains which differentiate them and what is the most common found in adults ?

Answer 2

1. HbA (97%) (2 alpha chains and 2 beta chains; α2β2 )
2. HbA₂ (2.5%) (2 alpha and 2 delta; α2δ2)
3. HbF (0.5%) (2 alpha and 2 gamma; α2γ2)

==> HbA is the main form of Hb in adults

Question 3

How many chromsomes do we have in the body ?

Answer 3

22 pairs and the X and Y chromosomes or XX in females ==> 46 chromosomes in the body

Note that chromsomes are paired

Question 4

What chromsome is the genes which code for alpha globin chains on and how many of them is there in the body?

Answer 4

Chromsome 16 (remember that there is essentially 2 chromosome 16’s as there paired)

There is 2 alpha genes per chromosome ==> 4 alpha genes in cell i.e. the body

Normal complement of alpha genes expressed as (αα/αα)

Question 5

What chromsome is are the genes which code for beta globin chains on and how many of them is there in the body?

Answer 5

Chromosome 11

There is 1 beta gene per chromosome ==> 2 beta genes per cell

Normal complement of beta genes expressed as (β/β)

Question 6

What happens to the genetic expression of globin coding genes throughout embryonic life and childhood ?

Answer 6

It changes

Question 7

What globin genes are expressed during:

1. Embryonic life
2. Foetal life
3. Adult (born)

Answer 7

1. Gower and portland
2. HbF - 2 alpha and 2 gamma
3. HbA, HbA₂ and HbF

Question 8

Describe what happens to Hb levels following birth and when the normal adult levels of

Answer 8

1. Small increase in delta chains produced because of HbA2
2. Massive increase in beta chains produced because of HbA
3. Massive decrease in gamma chains produced due to the drop in HbF produced

Question 9

What is a haemoglobinopathy ?

Answer 9

It is a hereditary condition affecting globin chain synthesis

Question 10

What are the 2 main haemaglobinopathy that we need to know about and describe the defect in globin chain synthesis they result in?

Answer 10

1. Thalassaemias; decreased rate of globin chain synthesis resulting in impaired haemoglobin production
2. Structural haemoglobin variants; normal production of structurally abnormal globin chain → variant haemoglobin eg HbS (end up with a different protein structure which has different physiological properties)

Question 11

In general in what fashion are haemaglobinopathies inherited ?

Answer 11

Autosomal recessive fashion

Question 12

What are the 2 main types of thalassaemia and synthesis of what type of globin chains is affected?

Answer 12

1. Alpha thalassaemia; α chains affected
2. Beta thalassaemia; β chains affected

Question 13

What type of anaemia does thalassaemia result in ?

Answer 13

Hypochromic microcytic anaemia - remember the inadequate globin synthesis will result in inadequate production of Hb

Also remember this is a problem with one of the components of haem hence a cytoplasmic defect and therefore microcytic

Question 14

Becuase the defect in different types of thalassaemia affects the synthesis one of the globin chains (remember need 2 diff globin chains to result in production of Hb) so one of the globin chains will be being made normally and the other will be being made defectively i.e. slowly, what does this unmatched globin synthesis result in ?

Answer 14

It results in damage to the RBC membranes, causing ineffective eryhtropoeisis and haemloysis while their still in the bone marrow

Question 15

Where is thalassaemia most common ?

Answer 15

In conuntries affected by malaria e.g. africa and south east asia

Question 16

Specifically what type of mutations cause alpha thalassaemia ?

Answer 16

Gene deletions

Question 17

Are all types of adult Hb affected in alpha thalassaemia?

Explain answer

Answer 17

Yes because alpha chains are involved in all froms of adult Hb

Question 18

Describe the classification of the 3 main types of alpha thalassaemia

Answer 18

The signs mean Reduced (α⁺) or absent (α⁰) synthesis of α chains

α thal trait; one or two genes missing:

• α+/α (-α/αα) - one alpha gene on one of the 2 chromosome 16’s is missing other chromosome has both alpha genes)
• α⁰/ α (–/αα) - 2 alpha genes on one of the chromosome 16’s is missing (other chromsome 16 has both alpha genes)
• α+/α+(-α/-α) - 1 alpha gene is missing on both of the 2 chromosome 16’s leaving each with only one functioning gene

HbH disease; only one alpha gene left on one of the chromosome 16’s α⁰/α+(–/-α )

Hb Barts hydrops fetalis; no functional α genes α⁰/α⁰ (–/–)

Question 19

Is there any treatment required for alpha thalassaemia ? and what are the clinical features of it if any and what is it important to distinguish from and how is this done?

Answer 19

It is asymptomatic and no treatment is needed

Can see on blood tests Microcytic, hypochromic red cells with mild anaemia

Important to distinguish it from iron deficiency anaemia - ferritin normal and red blood cell count raised

Question 20

What are the features of HbH disease - in terms of blood tests ?

Answer 20

Anaemia i.e. low Hb with very low MCV and MCH

Excess β chains form tetramers (β4) seen on the blood film - these cant carry O2

Red cell inclusions seen on special stain

Question 21

What are the clinical features of HbH disease ?

Answer 21

Moderate anaemia to maybe needing transfusion dependant

Splenomegaly due to extramedullary haematopoiesis

Jaundice due to:

• Haemolysis - intramedullary
• Ineffective erythropoiesis

Severe cases - transfusions +/- splenectomy

Commonest in S.E. Asia, Middle East and the Mediterranean where α⁰ is prevalent

Question 22

What is Hb Barts hydrops fetalis syndrome and what does it result in ?

Answer 22

• Severest form of α thalassaemia
• No α genes inherited from either parent α0/α0(–/–)
• Minimal or no α chain production →HbA can’t be made this is a disaster
• Hb Barts (γ4) and HbH (β4) majority of Hb at birth - both of which cant carry O2 ==> foetus cannot carry O2

Question 23

What are the clinical features of Hb Barts hydrops fetalis syndrome?

Answer 23

• Severe anaemia
• Cardiac failure
• Growth retardation
• Severe hepatosplenomegaly – seen in pic top R
• Skeletal and cardiovascular abnormalities
• They die in utero