Thalassemia is a hereditary blood disorder that results from inadequate production of haemoglobin, a vital component of red blood cells. Haemoglobin deficiency impairs the functionality of red blood cells. This results in a reduced lifespan and a decreased quantity of healthy red blood cells in circulation. Thalassemia can be categorized into alpha-thalassemia and beta-thalassemia. Let us learn about it!
The primary function of red blood cells is to transport oxygen to all the cells in the body. Oxygen is necessary for the proper functioning of cells as it serves as their source of energy. When the number of healthy red blood cells is insufficient, the delivery of oxygen to other cells is also compromised. This condition is known as anaemia. Fatigue, weakness, and shortness of breath may be caused by anaemia in affected individuals. Thalassemia may result in mild or severe anaemia, with severe cases potentially causing organ damage and even death.
Types of Thalassemia
When referring to the different “types” of thalassemia, two aspects are typically considered. Factors determining the type of thalassemia include the affected haemoglobin component (alpha or beta). Also, the condition’s severity is indicated by terms such as trait, carrier, intermedia, or major.
Haemoglobin is composed of two distinct components, namely alpha and beta. It plays a crucial role in transporting oxygen to all cells in the body. In cases where thalassemia is referred to as either “alpha” or “beta,” this pertains to the component of haemoglobin that is deficient. Low alpha is known as alpha thalassemia, while low beta is termed beta-thalassemia. Beta-globin chains are made by genes placed on chromosome 11.
Normal adults have three different forms of haemoglobin: HbA, HbA2, and HbF. HbA is made up of two alpha-globin subunits and two beta-globin subunits (α2; β2). HbA2 is made up of two alpha-globin subunits and two delta-globin subunits (α2; δ2). Also, HbF is made up of two alpha-globin subunits and two gamma-globin subunits (α2; γ2).
Types of Beta Thalassemia
Beta Thalassemia is further divided into three types: thalassemia major, intermedia, and minor. The most severe among these is thalassemia major in which the patient gets depended on the blood transfusion for survival.
1. Thalassemia major
It is the most grave form of beta thalassemia also known as, Cooley’s anaemia. It typically begins to manifest between 6 months and 2 years of age. Individuals with thalassemia major experience severe anaemia, which can result in symptoms such as heart failure, fatigue, and cachexia. The level of haemoglobin may drop to less than 7 g/dl and fetal haemoglobin to less than 90%. In response to the decreased levels of red blood cells, the bone marrow becomes overactive and can cause bone abnormalities, splenomegaly, and stunted growth. Consistent treatment with blood transfusions can cause iron overload leading to complications such as diabetes, hypothyroidism, hypopituitarism, hypoparathyroidism, cirrhosis, and arrhythmia.
2. Thalassemia intermedia
Thalassemia intermediate typically manifests between the ages of 2 and 6. It is characterized by milder anaemia compared to thalassemia major, with haemoglobin levels ranging from 7 to 9-10 g/dl. Patients can survive without transfusions or may require them only occasionally. As patients age, the expansion of bone marrow can lead to the development of various complications, such as growth retardation, bone abnormalities, and infertility. Additionally, hemolysis can result in an increase in iron levels in various tissues.
3. Thalassemia minor
It is also known as a thalassemia carrier/trait. It is the condition where an individual has one normal and one defective copy of the β globin gene. Thalassemia minor is typically observed during periods of physiological stress, pregnancy, or childhood. It is an asymptomatic condition, although mild anaemia may sometimes be present due to abnormalities in the shape of red blood cells. Beta-thalassemia minor or carriers often have Hb levels higher than 10g/dl. If both parents are carriers, there is a 25% chance of having a homozygous thalassemia child in each pregnancy.
Causes of Beta Thalassemia
Beta thalassemia arises from mutations, also known as variants, in the HBB gene. This gene provides instructions for the synthesis of beta-globin, a protein that constitutes one of the four subunits of haemoglobin.
Certain variants in the HBB gene obstruct the production of beta-globin, leading to a condition known as beta-zero (β0) thalassemia. Other variants permit some beta-globin production, but at a decreased rate, which results in beta-plus (β+) thalassemia. The presence of either β0 or β+ thalassemia alone does not necessarily indicate disease severity. However, individuals with either or both of these types have been diagnosed with thalassemia major or thalassemia intermedia.
Beta-globin deficiency disrupts haemoglobin production, hindering the normal development of red blood cells. When there is a shortage of mature red blood cells, the delivery of oxygen to tissues can be insufficient to meet the body’s energy demands. This lack of oxygen can cause poor growth, organ damage, and other health issues related to beta-thalassemia.
The HBB Gene
The HBB gene contains the genetic information to create a protein called beta-globin, which is a subunit of the larger protein haemoglobin found within red blood cells. Haemoglobin is made up of four protein subunits, typically two subunits of beta-globin and two subunits of alpha-globin, a protein created by the HBA gene. Heme, an iron-containing molecule, is attached to each protein subunit, and the iron in each heme can bind to one oxygen molecule. In the lungs, haemoglobin in red blood cells binds to oxygen molecules, and these cells carry the oxygen through the bloodstream to deliver it to tissues throughout the body.
Beta thalassemia is a prevalent blood disorder globally, with numerous infants born with the condition annually. The disorder is particularly common among individuals hailing from Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia.
Typically, individuals with moderate to severe types of thalassemia become aware of their condition during childhood, as they exhibit signs of severe anaemia early on. However, those with milder forms of thalassemia may only discover their condition when experiencing symptoms of anaemia or after undergoing routine blood testing or testing for other medical reasons.
As thalassemias are hereditary, the condition may be present in multiple members of the same family, leading some individuals to uncover their thalassemia due to a familial connection with the disease.
Individuals whose families originate from certain regions of the world are at a higher risk for developing thalassemia.
In thalassemia major and thalassemia intermedia, severe hemolysis results in overactivity of the spleen. The development of splenomegaly an early age can be prevented by regular blood transfusions. However, hypersplenism may develop in children between 5-10 years of age. Removal of the spleen is suggested when transfusion requirements exceed 200-220 ml RBCs/kg with 70% hematocrit or packed RBCs 250-275 ml/kg with 60% hematocrit per year. Splenectomy can protect patients against poor health and growth retardation by reducing the need for transfusions, improving Hb levels, and decreasing iron accumulation. Before surgical removal of the spleen, a meningococcal and pneumococcal vaccine is recommended, and after splenectomy, antimicrobial prophylaxis with penicillin is suggested to reduce the risk of infections.
The primary definitive treatment available for thalassemia patients is the transplantation of bone marrow. The first successful bone marrow transplant was performed in the 1980s, with a mortality rate of 3% and an 87% rate of thalassemia-free survival observed in young patients.
Blood transfusion therapy should be initiated upon confirmation of thalassemia diagnosis in case of severe anaemia to maintain haemoglobin levels in plasma and correct the resultant endogenous erythropoiesis in β-thalassemia major patients.
The only definitive therapies available for thalassemia patients remain gene therapy and bone marrow transplantation.
Beta-thalassemia is caused by changes in the beta-globin gene that lead to the complete absence or reduced synthesis of normal beta-globin chains. The lack of beta-globin chains and excess unmatched alpha-globin chains cause oxidative stress and early destruction of RBCs, resulting in severe anaemia.
- Ali, S., Mumtaz, S., Shakir, H. A., Khan, M., Tahir, H. M., Mumtaz, S., … & Khan, M. A. (2021). Current status of beta‐thalassemia and its treatment strategies. Molecular Genetics & Genomic Medicine, 9(12), e1788.
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