These lecture notes focus on Diagnostic Biochemistry and Hematology, particularly discussing Sickle Cell Anemia and Thalassemias. It delves into the structure of hemoglobin, the synthesis of various types of hemoglobin, and how genetic defects impact the production of normal hemoglobin chains.
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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
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