Beta Thalassaemia

Beta thalassaemias (β thalassaemias) are a group of inherited blood disorders characterised by reduced or absent synthesis of the beta chains of haemoglobin. The severity of the disease ranges from severe anaemia requiring lifelong transfusions to clinically asymptomatic individuals. The condition arises from mutations in the HBB gene, leading to decreased beta-chain synthesis, which in turn causes microcytic anaemia due to inadequate haemoglobin fill in red blood cells.

Beta thalassaemia genetics, the picture shows one example of how beta thalassaemia is inherited. The beta globin gene is located on chromosome 11. A child inherits two beta globin genes (one from each parent).

Overview

Types

Beta thalassaemia can be classified into three main forms:

1. Thalassaemia Minor: Usually asymptomatic or with mild symptoms of anaemia.
2. Thalassaemia Intermedia: Manages a normal life but may need occasional transfusions.
3. Thalassaemia Major: Severe anaemia requiring lifelong blood transfusions.

Signs and Symptoms

Individuals with beta thalassaemia major typically present within the first two years of life with severe anaemia, poor growth, and skeletal abnormalities. Untreated, it often leads to death by heart failure. Beta thalassaemia intermedia presents later with mild to moderate anaemia symptoms. Beta thalassaemia minor is usually asymptomatic, though some may have mild anaemia. Complications can include liver cirrhosis, heart failure, growth impairment, diabetes, osteoporosis, and more.

Cause

Beta thalassaemia is caused by mutations in the HBB gene, leading to two major groups of mutations:

• Nondeletion forms: Typically involve single base substitutions or small insertions.
• Deletion forms: Different sizes of deletions affecting the β globin gene.

Mutations are classified as (βo) if they prevent any formation of β globin chains and (β+) if they allow some β globin chain formation.

Diagnosis

Peripheral blood smear from a person with beta thalassaemia. The red blood cells vary greatly in shape and size and some look empty because of their low haemoglobin content (Giemsa stain).

Diagnosis involves:

• Complete Blood Count (CBC): Reveals microcytic anaemia.
• Haemoglobin Electrophoresis: Shows increased haemoglobin A2 and F.
• DNA Analysis: Detects deletions and mutations.

Prevention

Beta thalassaemia can be prevented through carrier screening and prenatal diagnosis. Screening programmes have successfully reduced incidence rates in certain regions.

Treatment

Beta Thalassaemia Major

Surgically removed spleen of a thalassaemic child. It is about 15 times larger than normal.

Regular lifelong blood transfusions are required. Advances in iron chelation treatments (deferoxamine, deferiprone, deferasirox) help manage iron overload due to transfusions. Bone marrow transplantation can be curative. Gene therapy and gene editing strategies are emerging treatments.

Surgical

Splenectomy may be necessary in cases of hypersplenism, though its use is declining due to improved transfusion protocols.

Therapeutic

Long-term transfusion therapy aims to maintain haemoglobin levels and prevent bone marrow hyperactivity. Leucoreduced blood transfusions are preferred to reduce adverse reactions.

Pharmaceutical

Iron chelation therapy is very important to prevent iron overload. The primary chelators include deferoxamine, deferiprone, and deferasirox. Luspatercept is a newer treatment for reducing transfusion burden in adults with transfusion-dependent beta thalassaemia.

Beta Thalassaemia Intermedia

Patients may require episodic transfusions and chelation therapy in case of iron overload. Genetic counselling is recommended.

Beta Thalassaemia Minor

Usually asymptomatic, these patients often do not require treatment but should be monitored, particularly if coexisting conditions such as chronic hepatitis or liver disease are present.

Epidemiology

Beta thalassaemia is prevalent among Mediterranean peoples, with high incidence rates in Greece, Turkey, and the major Mediterranean islands. The disorder is most common in areas known as the "thalassaemia belt," including regions in Sub-Saharan Africa, the Mediterranean, the Middle East, and Southeast Asia. In the United States, the prevalence is approximately 1 in 272,000 people.

Evolutionary Adaptation

The thalassaemia trait may offer some protection against malaria, providing a selective survival advantage in regions where malaria is or was prevalent.

Self-assessment MCQs (single best answer)

Which gene mutation causes beta thalassaemia?

score 0 / 1. running total: 0 / 0

What is the primary cause of microcytic anaemia in beta thalassaemia?

score 0 / 1. running total: 0 / 0

Which form of beta thalassaemia typically requires lifelong blood transfusions?

score 0 / 1. running total: 0 / 0

What is the main diagnostic method for detecting beta thalassaemia mutations?

score 0 / 1. running total: 0 / 0

Which of the following is not a complication of untreated beta thalassaemia major?

score 0 / 1. running total: 0 / 0

What is the main treatment goal for patients with beta thalassaemia major?

score 0 / 1. running total: 0 / 0

Which therapeutic agent is used to manage iron overload in beta thalassaemia patients?

score 0 / 1. running total: 0 / 0

In which regions is beta thalassaemia most prevalent?

score 0 / 1. running total: 0 / 0

What is the common presentation of beta thalassaemia major in the first two years of life?

score 0 / 1. running total: 0 / 0

What evolutionary advantage is associated with the thalassaemia trait?

score 0 / 1. running total: 0 / 0