Week 3: Haemoglobinopathies

Question 1

What are haemoglobinopathies

Answer 1

• Genetic disorders of the Hb of the rbc
• Commonest single gene disorders in the world + follows classic Mendelian/Monogenic inheritance
• Commonly associated in areas of LIC or where malaria is prevalent

Question 2

Reminder of the Hb molecule

Answer 2

• Tetrameric molecule made up of 2 alpha-like + 2 beta-like globin chains
• Each globin chain has 1 haem group inserted
• If the interactions between the chains are incorrectly orientated, O2 will not be picked up

Question 3

Mutations in coding regions (exons) results in:

Answer 3

Altered structure of protein

Question 4

Mutations in the non-coding regions (introns) results in:

Answer 4

Altered quantity of protein

Question 5

Thalassaemia syndromes

Answer 5

• An alteration to globin synthesis
• Caused by gene deletion/mutation in non-coding regions

Question 6

Hereditary persistence of foetal Hb (HPFH)

Answer 6

• Where fetal Hb is continued into adulthood, possessing altered structure, a thalassaemia-like syndrome

Question 7

Human Hb variants

Answer 7

Can be caused by single aa substitution, aa deletions of 1 or more, cross-over between 2 single substitiutions, frameshift, chain termination mutation or fusion chains

Question 8

Examples of Human Hb variants

Answer 8

• Hbc Harlem (Cross-over between 2 single substitutions)
• Hb Grady (Frameshift)
• Hb Constant Spring (Chain termination mutation)
• Hb Kaya Dora (Chain termination mutation)
• Hb Icaria (Chain termination mutation)
• Hb Lepore/anti-lepore (Fusion chain of delta-beta/beta-delta respectively)
• Hb Kenya/anti-Kenya (Fusion chain of gamma-beta/beta-gamma respectively)

Question 9

Clinical disorders caused by structural variants

Answer 9

• Sickling cell disorder (HbS)
• Haemolysis due to HbC/HbE/HbD
• Unstable Hb
• Abnormal O2 binding
• Altered synthesis

Question 10

Types of thalassaemia

Answer 10

• alpha-thalassaemia
  + a+ = Reduced synthesis
  + a0 = No synthesis
• beta-thalassaemia
  + b+ = Reduced synthesis
  + b0 = No synthesis
• delta-beta-thalassaemia
• epsilon-gamma-delta-beta-thalassaemia
• delta-thalassaemia
• Hb lepore

Question 11

Pathophysiolopgy of thalassaemia

Answer 11

• Caused by imbalanced globin chain synthesis, often forming non-telameric structures that + leaks out of the cell
• Clinical problems can result from not enough functional Hb or from the effects of excess chains

Question 12

a-thalassaemia

Answer 12

• a0 arises from gross deletion of 1 or more genes, or deletion of non-coding regions
• a+ arises from gross deletion or non-deletion
• Can be inherited by Mendelian means
• Many deletion forms of a-thalassaemia have been found for a0 + a+
• Mutations affect the RNA processing + RNA translation

Question 13

b-thalassaemia

Answer 13

• Many types of mutations can result in different variants of b-thalassaemia
• Gross gene deletion resulting in no mRNA
• Chain termination mutation + frameshift results in a non-functional mRNA
• Loss of splice joints, generation of new splice junction, activation of cryptic splice sites, polyA addition signal mutations result in Defective mRNA splicing
• Mutations in 5’ regulatory region result altered rate of protein synthesis
• Mutations in codons result in unstable proteins

Question 14

Prognosis + Treatment of thalassaemia

Answer 14

• Preventing the genetic disease can be done by antenatal + genetic counselling
• Treatment of genetic disease can involve long-term transfusion + gene therapy to reverse the development switch in patient genetics, althought he latter option is arguable still questionable