An introduction of Thalassimia –Genetic disorder

Thalassemia is a complex Autosomal recessive blood disorder that inherits from parents to the offspring. In Thalassemia, the body makes an abnormal form or inadequate amount of haemoglobin. The disorder results in destroying RBCs in large numbers that leads to anaemia. Before we understand thalassemia, one has to understand the basic structure and function of haemoglobin.

Haemoglobins- structure & function

Red Blood Cells (RBCs) contain haemoglobin that is essential for human life as it transport blood oxygen to tissues.  Similarly, it transports carbon dioxide from tissue to blood (fig-1) and also maintain pH.  Haemoglobulin is the iron containing protein and consists of two parts; haem and globin. Haem carries oxygen where Globin protects haem from oxidation. Haemoglobin remains in two stages; oxygenated state (bright red) called oxyhemoglobin and oxygen reduced stage (purplish blue).  Haemoglobin are developed in bone marrow RBCs. When RBC dies, haemoglobin is broken in iron and bilirubin. Iron is saved and transported to bone marrow by the transferrin protein for reuse in synthesis of RBCs whereas, bilirubin, a chemical that is excreted into the bile and give yellowish colour to the faeces.

Haemoglobin is a protein of four polypeptide chains (α1, α2, β1, and β2). Each chain is attached to a heme group composed of porphyrin (ring like structure) attached with iron (fig-2).  These iron-porphyrin complexes coordinate oxygen molecules.

Symptoms of thalassemia

The symptoms vary depending on the severity of the thalassemia but main symptom is anaemia.   Mild affected people exhibit mild anaemia or may have any symptoms. Intermediate forms of thalassemia can exhibit mild to moderate anaemia which may be associated with other health problems like slow growth, delayed puberty, bone problems, enlarged spleen, etc., people with severe thalassemia experiences severe anaemia, poor appetite, paleness, dark urine, yellow discoloration of skin (jaundice), and enlarged liver or heart.

Genetic cause of disorder

Thalassemia occurs when there is a defect in a gene controls production of any of these four polypeptide chains (α1, α2, β1, and β2). There are three main types of thalassemia;  alpha, beta and minor thalassemia. Alpha thalassemia is caused by mutations in the HBA1 and/or HBA2  genes, while beta thalassemia in HBB gene.

Alpha thalassemia: there aretwo types of α-thelassimia which can cause health problems and occurs worldwide.

  1. Haemoglobin Bart hydrops fetalis syndrome or Hb Bart syndrome or major thalassemia is more severe is characterized by a condition in which excess fluid builds up in the body before birth.  Other signs may include severe anaemia, an enlarged liver and spleen, heart defects, associated with abnormalities of the urinary system or genitalia. Since babies have serious health issue they tend to die immediately after birth or still born. The syndrome can also cause serious complications for women during gestation that includes high blood pressure, swelling, premature delivery and abnormal bleeding.
  2. HbH disease is mild to moderate causes anaemia, spleen enlargement and jaundice sometimes associated with bone deformities. The symptoms of the disease usually appear in early childhood, but affected individuals typically live into adulthood.

Alpha thalassemia typically results from deletions in HBA1 and HBA2 genes. Both of these genes provide instructions for making a protein called alpha-globin, a component (subunit) of haemoglobin. These two alpha-globin genes are located close together in a region of chromosome 16 (16p13.3) known as the alpha-globin locus. HBA1 gene is about 842 base pairs with 3 exons. Similarly HBA2 gene is about 834 base pairs with 3 exons. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5′ untranslated regions and the introns, but they differ significantly over the 3′ untranslated regions. Rarely, mutations in or near these genes can also be responsible for the disease. The signs and symptoms of alpha thalassemia tend to be more severe when the disease results from mutations in the alpha-globin genes than when it is caused by deletions of these genes. The inheritance of alpha thalassemia is complex. Each person inherits two alpha-globin alleles from each parent. If both parents are missing at least one alpha-globin allele, their children are at risk of having alpha thalassemia trait. The precise risk depends on how many alleles are missing and which combination of the  HBA1  and  HBA2  genes is affected as shown in fig-3.

Beta thalassemia:  there aretwo types of β-thelassimia which can cause health problems and occurs worldwide.

  1. Thalassemia major or Cooley’s anemia is more severe. The signs and symptoms appear within the first 2 years of life. Children develop life-threatening anaemia and do not gain weight and grow as compared to normal. They may develop jaundice. Affected individuals may have an enlarged spleen, liver, and heart, and their bones may be defective. Young kids with thalassemia major exhibit delayed puberty. Many patients with thalassemia major need frequent blood transfusions to maintain their normal red blood cells.
  2. Thalassemia intermedia are milder as compared to thalassemia major. The signs and symptoms of thalassemia intermedia appear in early childhood or later in life. Affected individuals have mild to moderate anaemia and may also have slow growth and bone abnormalities.

Mutations in the  HBB gene cause beta thalassemia. The HBB gene provides instructions for making a protein called beta-globin that is subunit of haemoblobin. The gene is located on 11p15.4. The gene size is 1607 base pairs with 3 exons. Nearly 400 mutations in the HBB gene have been found to cause beta thalassemia. Most of the mutations involve a change in a single nucleotide within or near the HBB gene. Other mutations insert or delete a small number of nucleotides in the HBB gene. Thalassemia major and thalassemia intermedia are inherited in an  autosomal recessive pattern. The carrier patients (one copy of the mutant gene) do not show signs and symptoms of the disease. However, sometimes people with only one HBB gene mutation exhibit mild anaemia and they are said to be thalassemia minor. Some mutations in the HBB gene prevent the production of any beta-globin. The absence of beta-globin is referred to as beta-zero (β 0) thalassemia or major. Other HBB gene mutations allow some beta-globin to be produced, but in reduced amounts. A reduced amount of beta-globin is called beta-plus (B +) thalassemia or intermedia. Having either a beta-zero or beta-plus thalassemia does not necessarily reveal disease severity.


Blood transfusion is the main treatment for people with severe alpha and beta thalassemia. This treatment provides healthy red blood cells with normal haemoglobin. Because red blood cells only live about three months, repeated transfusions may be needed to maintain a healthy supply of red blood cells.