Understanding Thalassemia: Genetic Mutations, Haemoglobin Production, Symptoms & Treatment

It is common in many countries and one of the commonest single gene diseases. It is estimated that 12000 children are born with thalassemia major in India

Thalassemia is a genetic disease due to mutation in the genes encoding the globin chain of hemoglobin protein which forms the red pigment of blood. This leads to anemia due to ineffective ërythropoiesis" or formation of blood in bone marrow. This leads to enlargement of liver and spleen and bone changes leading to "chipmunk facies".  

The name thalassemia is derived from the Greek words Thalassa means sea and haima means blood, because this disease was first observed in countries around the Mediterranean Sea. However, it is common in many countries and one of the commonest single gene diseases. It is estimated that 12000 children are born with thalassemia major in India.

What are the different types of thalassemia and the symptoms associated?

There are two major types of thalassemia genetically, alpha thalassemia (mutation in alpha globin genes HbA1 and HBA2) and beta thalassemia (mutation in beta globin gene namely HBB). Beta thalassemia major is the severe form which usually presents in childhood and require monthly blood transfusions for survival. Beta thalassemia intermedia children require less frequent transfusions. Thalassemia minor or carriers present only with mild anemia, jaundice and do not usually require transfusions. 

Alpha thalassemia in its severest form present as hydrops fetalis in the pregnancy due to Hemoglobin Bart (swollen baby due to accumulation of fluid in bodily cavities due to severe anemia). Another form of alpha thalassemia is HbH disease which presents in varied forms, severe to moderate anemia and present in childhood or even adulthood. Alpha thalassemia minor can have mild anemia or be asymptomatic.

What are genetic mutations that cause Thalassemia?

Alpha thalassemia is caused by mutations in alpha globin genes which are four in number. Alpha thalassemia minor occur due to deletion of one or two alpha genes, HbH disease occurs due to deletion of three genes and hydrops fetalis occurs due to deletion of all four genes. Common single alpha gene deletions are 3.7 kilobase and 4.2 kilobase deletion. Common double alpha gene deletions are Southeast Asian deletion and Meditteranean deletion. 

There are more than 100 mutations in HBB gene causing beta thalassemia of which common are point mutations such as premature termination of protein, splice site mutation frameshift mutations, 619 basepair deletion, etc. Tests such as haemoglobin variant analysis by paper electrophoresis or HPLC can screen for thalassemia.  Beta thalassemia major/ intermedia patients have elevated HBF, minor patients have elevated HbA2. 

The mutations can be detected by various DNA tests such as ARMS PCR, Sanger sequencing, MLPA and next generation sequencing. The genetic inheritance pattern in thalassemia is autosomal recessive, mutation in one copy of HBB gene leads to minor or carrier state. In case two carriers marry, there is a 25 percent chance of transmission of thalassemia major/intermedia (both HBB genes mutated) in every pregnancy.     

Treatment and Prevention

Treatment is by regular blood transfusions. Accumulation of iron is prevented by oral or subcutaneous iron chelating agents such as deferiprone, deferasirox or desferrioxamine. Thalassemia can be diagnosed in pregnancy (prenatal diagnosis) by fetal DNA mutation analysis after chorionic villus sampling or amniocentesis around 12 to 16 weeks of pregnancy. Knowledge of mutations in the family is preferred to know before the family plans a pregnancy. Invitro fertilisation (test tube baby) and preimplantation genetic diagnosis is also possible by embryo DNA diagnosis. 

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