Diagnostic Biochemistry and Haematology – Week 2
Lecture – Sickle Cell Anaemia and the Thalassaemias
Review of Haemoglobin Molecule
Haemoglobin (Hb)
• tetramer of 4 globin chains
• two different pairs each with own haem group
• each haem contains Fe2+
Most adult blood contains 3 types of Hb:
1) Hb A = α2β2 (96.0-98.0%)
2) Hb F = α2γ2 (0.5-0.8%)
3) Hb A2 = α2δ2 (1.5-3.2%)
• There are 2 groups of alpha and 2 groups of beta → most
common form → haemoglobin a
• Most adults have haemoglobin F → foetal haemoglobin 2 alpha
and 2 gamma chains
• Haemoglobin A2 → 2 alpha and 2 delta chains
• The chains are always in two pairs → the iron is the red part of the molecule
Haemoglobin synthesis with age
• α-globin (----- )
• expressed in
foetal life;
production
maintained
• β-globin (-----)
• expressed at
low level in
early foetal life
• increased
production after
birth; switch to
adult Hb (α2β2)
• largely replaces γ chain (---------) 3-6 months after birth
• In the embryonic form → blue and purple on the left → zeta and epsilon chains → two of each
• There are 4 types of foetal haemoglobin
• The foetal haemoglobin are unstable
• The alpha globin production starts the earliest
• The gamma chain production starts second
• Beta chain starts third
• The gamma haemoglobin and beta haemoglobin switch the amount of production
1
,Haemoglobinopathies
• Genetic defects of Haemoglobin
o most common genetic disorders
worldwide
o occurred in tropical and subtropical
areas before population
movements Geographical distribution of common
• The haemoglobinopathies are inherited haemoglobinopathies
• The development of the different
haemoglobin types and
haemoglobinopathies are believed to have developed to have a protective effect for malaria →
the parasite is not able to complete its cycle
• Inherited Haemoglobin (Hb) abnormalities result from:
1) synthesis of a structurally abnormal Hb
• caused by a single or multiple amino acid substitution in α- or β-globin
• Mutation position affects the way the hemoglobin functions. e.g. Sickle cell anemia (Hb SS)
2) reduced rate of synthesis of normal α- or β-globin chains
• heterogeneous group of genetic disorders - Thalassemias
QUESTION
Are these the only genetic defects which cause anaemia?
• Haemoglobinopathies re divided into two groups
• Group 1 → Most common → amino acid substitution in one of the chains either beta or alpha
• The severity depends on the location of the point mutation as this can affect molecule stability,
oxygen retention ability etc
• Group 2 → reduced synthesis of the chains
Haemoglobin synthesis
• Genes for globin chains occur in 2 clusters:
• globin genes arranged in order they are expressed
• α-globin gene is duplicated (α1 and α2)
• both genes on each chromosome are active
• The amounts of α- and β globin is balanced
• Chromosome 16 and 11 are involved in the hameoglobin syntesis
2
, • Chromosome 16 → zeta and alpha production
• Chromosome 11 → epsilon, Gamma, delta and beta
• The order is in which they are expressed
• Alpha globin → both of the genes are active
• A balanced amount of alpha and beta globin is required for correct haemoglobin
β Thalassaemias
• Heterogeneous group of
genetic disorders
o result from reduced rate
of normal α or β chain
synthesis
• β-Thalassaemia syndromes
o β-Thalassaemia major - β0 thalassaemia.
▪ No β globin production
• Thalassaemia intermedia – β+ thalassaemia.
o Some beta globin production
• β-Thalassaemia trait (minor/ carrier)
• δβ-Thalassaemia - Failure to produce β and δ chains
Thalassaemia can occur in combination with mutations –
• Hb Sβ-Thalassaemia
• Beta thalassaemia major → no beta globin chain production → no beta globin
• Thalassaemia intermedia → some beta is produced but there is a inbalance
• Beta thalassaemia trait minor and carrier are the same thing
• Delta thalassemia → no beta and delta chains
• There can be a point mutation and a decrease in production → S beta thalassaeimia
β-Thalassaemia major
• No β chain (β0) or small amounts (β+) synthesised
• Excess α chains precipitate in RBC oxidize cell membrane proteins and lipids (hemichromes)
• cause severe ineffective erythropoiesis and haemolysis
• > α chain excess, the more severe the anaemia
• >400 genetic defects detected in β-Thal major
• No balance with alpha chains → no beta to pair with
3
Lecture – Sickle Cell Anaemia and the Thalassaemias
Review of Haemoglobin Molecule
Haemoglobin (Hb)
• tetramer of 4 globin chains
• two different pairs each with own haem group
• each haem contains Fe2+
Most adult blood contains 3 types of Hb:
1) Hb A = α2β2 (96.0-98.0%)
2) Hb F = α2γ2 (0.5-0.8%)
3) Hb A2 = α2δ2 (1.5-3.2%)
• There are 2 groups of alpha and 2 groups of beta → most
common form → haemoglobin a
• Most adults have haemoglobin F → foetal haemoglobin 2 alpha
and 2 gamma chains
• Haemoglobin A2 → 2 alpha and 2 delta chains
• The chains are always in two pairs → the iron is the red part of the molecule
Haemoglobin synthesis with age
• α-globin (----- )
• expressed in
foetal life;
production
maintained
• β-globin (-----)
• expressed at
low level in
early foetal life
• increased
production after
birth; switch to
adult Hb (α2β2)
• largely replaces γ chain (---------) 3-6 months after birth
• In the embryonic form → blue and purple on the left → zeta and epsilon chains → two of each
• There are 4 types of foetal haemoglobin
• The foetal haemoglobin are unstable
• The alpha globin production starts the earliest
• The gamma chain production starts second
• Beta chain starts third
• The gamma haemoglobin and beta haemoglobin switch the amount of production
1
,Haemoglobinopathies
• Genetic defects of Haemoglobin
o most common genetic disorders
worldwide
o occurred in tropical and subtropical
areas before population
movements Geographical distribution of common
• The haemoglobinopathies are inherited haemoglobinopathies
• The development of the different
haemoglobin types and
haemoglobinopathies are believed to have developed to have a protective effect for malaria →
the parasite is not able to complete its cycle
• Inherited Haemoglobin (Hb) abnormalities result from:
1) synthesis of a structurally abnormal Hb
• caused by a single or multiple amino acid substitution in α- or β-globin
• Mutation position affects the way the hemoglobin functions. e.g. Sickle cell anemia (Hb SS)
2) reduced rate of synthesis of normal α- or β-globin chains
• heterogeneous group of genetic disorders - Thalassemias
QUESTION
Are these the only genetic defects which cause anaemia?
• Haemoglobinopathies re divided into two groups
• Group 1 → Most common → amino acid substitution in one of the chains either beta or alpha
• The severity depends on the location of the point mutation as this can affect molecule stability,
oxygen retention ability etc
• Group 2 → reduced synthesis of the chains
Haemoglobin synthesis
• Genes for globin chains occur in 2 clusters:
• globin genes arranged in order they are expressed
• α-globin gene is duplicated (α1 and α2)
• both genes on each chromosome are active
• The amounts of α- and β globin is balanced
• Chromosome 16 and 11 are involved in the hameoglobin syntesis
2
, • Chromosome 16 → zeta and alpha production
• Chromosome 11 → epsilon, Gamma, delta and beta
• The order is in which they are expressed
• Alpha globin → both of the genes are active
• A balanced amount of alpha and beta globin is required for correct haemoglobin
β Thalassaemias
• Heterogeneous group of
genetic disorders
o result from reduced rate
of normal α or β chain
synthesis
• β-Thalassaemia syndromes
o β-Thalassaemia major - β0 thalassaemia.
▪ No β globin production
• Thalassaemia intermedia – β+ thalassaemia.
o Some beta globin production
• β-Thalassaemia trait (minor/ carrier)
• δβ-Thalassaemia - Failure to produce β and δ chains
Thalassaemia can occur in combination with mutations –
• Hb Sβ-Thalassaemia
• Beta thalassaemia major → no beta globin chain production → no beta globin
• Thalassaemia intermedia → some beta is produced but there is a inbalance
• Beta thalassaemia trait minor and carrier are the same thing
• Delta thalassemia → no beta and delta chains
• There can be a point mutation and a decrease in production → S beta thalassaeimia
β-Thalassaemia major
• No β chain (β0) or small amounts (β+) synthesised
• Excess α chains precipitate in RBC oxidize cell membrane proteins and lipids (hemichromes)
• cause severe ineffective erythropoiesis and haemolysis
• > α chain excess, the more severe the anaemia
• >400 genetic defects detected in β-Thal major
• No balance with alpha chains → no beta to pair with
3
