Thalassaemia can be found in any population of people but is most common in the Chinese and Malays in Malaysia, people from the South East Asia, Mediterranean & the Middle East. In Malaysia it is seen in 3 to 5% of Malays, Orang Asli and Chinese. HbE is seen in Malays & Orang Asli 3 to 5%.
Normal adult haemoglobin (HbA) has 2 alpha globin chains and 2 beta globin chains. There are 2 types of Thalassaemia
- Alpha (α) thalassaemia - lack of alpha globin chains
- Beta (β) thalassaemia - lack of beta globin chains
Thalassaemics pass down the gene to their offspring & may present as
- thalassaemia trait or - usually healthy and most go through life unaware of their status thalassaemia minor
- thalassaemia - occurs if two thalassaemia minors marry intermedia
- thalassaemia major - occurs if two thalassaemia minors marry
Clinical Classification of α and β Thalassaemia
|Minor (Hb normal)
(Hb 6 to 9g/dl)
HbH with HbCS
|β thal intermedia
|Major (Hb < 5g/dl)
|Homozygous beta (β)
There are 4 Alpha genes, 2 on each chromsome.
Types of alpha thalassaemia:
- α+ thalassaemia or silent alpha thalassaemia (minor / trait) - 1 gene missing
- α° thalassaemia or alpha thalassaemia minor (minor / trait) - 2 genes missing on the same chromosome
- HbH disease - 3 genes deletion
- Alpha thalassaemia major (causes hydrops foetalis in Chinese) - 4 genes missing
α° thal trait
When MCV is < 76fl, MCH < 26pg, TRBC > 5m. and Hb analysis is normal, α° thalassaemia trait is tested for by doing the following test:
- Parents FBC, MCV - one parent has MCV < 76fl, MCH < 26pg and Hb analysis is normal
- *S.Ferritin* - normal to high levels of storage iron
- *DNA studies for α° thalassaemia
Types of beta thalassaemia:
- Beta (β) thalassaemia trait / minor
- Beta (β) thalassaemia intermedia
- Beta (β) thalassaemia major
Malays: β+ (reduced βchains): 50% have mutation IVS 1-5 (G to C)
Chinese: β° (no β chains): 49.8% mutation 41-42 (-TCTT)
β thalassaemia minor / trait is not serious. People with thalassaemia minor are healthy and do not have any effects on health or length of life.
β thalassaemia major is serious and may occur when two thalassaemia minors marry and have children. Beta thalassaemia major suffers from severe anaemia and needs treatment (red cell transfusions monthly and chelating agent like deferral) all their lives. There is no cure for thalassaemia major. Bone marrow transplant for beta thalassaemia major, if successful, may result in normal Hb formation and there will be no need for transfusions. Gene therapy may one day be available to "cure" thalassaemia but it is not yet available.
Is a point mutation with 1 amino acid substitution that changes the structure and function of the Hb molecule. Example of haemoglobinopathies are HbE, HbS, Hb Constant Spring (HbCS).
HbE has a point mutation at codon 26 of β globin chain with GAG changed to AAG changing amino acid from Glutamatic Acid to Lysine amino acid.
It is seen mainly in Malays (3.5-4.5%), Orang Asli & those in the Golden Triangle area.
The heterozygous HbE combined with β thalassaemia trait give rise to HbE/β Thal (Thal Intermedia)
HbS is a mutation at codon 6 of β globin chain: Here amino acid Glu is changed to Val.
HbS is rare in Malaysia.
Hb Constant Spring (HbCS) has a point mutation at stop codon of the α globin chain, changing amino acid TAA to CAA:
- This results in an extra long globin chain with an additional 41 amino acids making the normally 131 α globin chain to become 172 amino acids long.
- HbCS is seen in Malays and Chinese - not in Indians
- Homozygous, combined with α1 or α° thal it is HbH disease, thalassaemia intermedia.
Laboratory Tests for Diagnosing Thalassaemia
- FBP-Hb, PCV, MCV, MCH
|MCV < 76 fl
MCH < 27
||Commonly due to
- Reticulocyte smear - for "H" inclusions for α° Thal
- Hb electrophoresis or HPLC - for β thal, HbE, HbS,HbCoSp, HbH,Hb Barts, HbNY, HbD
- S. Ferritin: High in Thalassaemia & multiply transfused persons
- DNA studies for α° thalassaemia
Additional Tests that should be done for Multiply Transfused are:
- RBC genotype at diagnosis,
- Screen for HBsAg, anti-HCV, anti-HIV initially & annually,
- LFT - for transaminases done initially & annually.
Thalassaemia is a public health problem in Malaysia.
Suggested Flow for Screening those with a Low MCV, MCH
HbCS - normal MCV, MCH
HbE - MCV < 80fl, MCH < 26pg
When a person is identified with thalassaemia, screening their blood relatives would identify more of those with thalassaemia.
More cost effective than population screening. Screen the patient's parents, siblings, children and other blood relatives of those with thalassaemia. Spouse can be screened for thalassaemia to assess the risk for thalassaemia major.
Risk for Thalassaemia Major if
- α° thalassaemia marries α° thalassaemia or
- β thalassaemia trait marries a β thalassaemia trait and has children
Risk for Thalassaemia Intermedia if
- β thalassaemia marries HbE and has children
- HbCS marries α° thalassaemia trait and has children
Prevention of Thalassaemia
FBC - Hb near normal; MCV, MCH if low, MCHC high, high rbc
- S. Ferritin
- Hb electrophoresis / HPLC: HbA2, HbF, HbE, HbS, HbCS, HbH
- Reticulocyte smear: "H" inclusions for α° thalassaemia
- DNA studies for α° thalassaemia
- Prenatal Diagnosis: foetal blood sampling, foetal DNA by chorionic villi sampling
- Counselling - marriage of traits!
- Give a verbal and written (laminated) result