10. Haemoglobinopathies

Question 1

What is Hb?

Answer 1

Iron containing protein in RBCs that carries oxygen

Normal Hb consists of 2 alpha chains and 2 beta chains

Question 2

What causes haemoglobinopathies?

Answer 2

Mutations in globin genes that cause:

Change in structure and quality of Hb

or

Reduction in quantity of Hb due to reduced synthesis of a chain, leading to imbalance

Question 3

Describe the alpha and beta globin genes

Answer 3

2x α globin genes on chr16 (HBA1 & HBA2) –> 4 genes per diploid cell

1x β globin gene on chr11 (HBB)

Question 4

What are the different types of Hb in adult blood?

Answer 4

HbA (α2β2), HbF (α2γ2), HbA2 (α2δ2)

Question 5

What are the two clinically relevant forms of alpha thalassaemia?

Answer 5

1. Hb Barts hydrops fetalis - deletion of 4 alpha globin genes
2. HbH - deletion of 3 alpha globin genes

10% due to SNVs in HBA1 (α α +) or HBA2 (α +α )

Question 6

What causes deletions of α globin genes?

Answer 6

Unequal crossing over due to high homology in α -globin gene cluster

Causes most common form of α+ thalassaemia (α 3.7 and α 4.2)

Question 7

At the cellular level, what is the effect of a decrease in α globin production?

Answer 7

Excess of beta globin chains cause hypochromic, microcytic cells

Decreased mean cell Hb (MCH) and mean cell volume (MCV)

RBCs increase to reach normal Hb level - can’t be maintained –> anaemia

The 4 α globin genes are active early in fetal life - problematic for unborn child

Question 8

What is the effect of one α globin deletion?

Answer 8

α+ carrier - asymptomatic, no anaemia

Question 9

What is the effect of two α globin deletions and what is the phenotype?

Answer 9

Homozygous α+ thalassaemia (deletions on different alleles)

or

Heterozygous α0 thalassaemia (deletions on same allele)

Asymptomatic but microcytic anaemia and hypochromic RBCs

Important to distinguish between the 2 for risk

Question 10

What is the effect of three α globin deletions?

Answer 10

HbH disease

Excess of β globin –> abnormal Hb that can’t effectively carry oxygen

Question 11

What is the clinical phenotype of 3 Alpha globin gene deletions?

Answer 11

Often presents in adulthood

Microcytic anaemia, extravascular haemolysis, splenomegaly

Question 12

What is the effect of four α globin deletions?

Answer 12

Hb Barts Hydrops Fetalis syndrome

Still birth/early neonatal death

Question 13

What causes beta thalassaemia and what is the effect of different mutation types?

Answer 13

Biallelic mutations in HBB (mainly SNVs)

Cause reduced/absent β globin chain synthesis

• LoF cause β-zero thal - no output from affected allele
• Promoter, polyadenylation signal cause β-plus thal - variable output

Question 14

What are the four types of beta thalassaemia?

What are the clinical implications of each?

Answer 14

1. β-thal major - severe anaemia, hepatosplenomegaly, affected from 6 months, transfusion dependent within 2 years
2. β-thal intermedia - later presentation, mild anaemia, occasional transfusions
3. β-thal carriers (minor) - asymptomatic but microcytic/hypochromic RBCs
4. Dominant β-thal - rare variants cause unstable β-globin chains that precipitate in erythroid precursors

Question 15

What is Hb Constant Springs?

Answer 15

Variant located in the stop codon of HBA2

Leads to an elongated α-globin chain - produced in very small amounts because its mRNA is unstable.

Question 16

What causes sickle cell disease?

Answer 16

Presence of at least one HbS allele (HBB Glu6Val) + second HBB mutation

Majority of cases are homozygous for Glu6Val

Question 17

What is the phenotype of SCD?

Answer 17

Vaso-occlusive events (RBCs block blood flow, tissue deprived of oxygen) - acute, chronic pain and organ damage

Chronic hemolytic anemia

Question 18

What testing is done prior to genetics for haemoglobinopathies?

Answer 18

Full blood count - shows haemolytic anaemia

HPLC / isoelectric focusing to characterise Hb profile (amounts of HBA, HbF & HBA2)