Summary

Beta thalassemia is a genetic blood disorder that affects the production of hemoglobin, a protein in red blood cells that carries oxygen throughout the body. It is caused by HBB gene mutations, which provide instructions for making beta-globin, one of the two globin chains that make up hemoglobin. 

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Overview

Beta thalassemia is a genetic blood disorder caused by mutations in the HBB gene that affect the production of hemoglobin. It is most commonly found in people of Mediterranean origin, especially those from Cyprus (highest carrier frequency), Italy, Greece, Middle East, and Southeast Asia. It has a global prevalence of around 1.5%, with approximately 60,000 symptomatic individuals born annually. Beta thalassemia has three main forms: minor, intermediate, and major. Symptoms of beta thalassemia include fatigue, dizziness, pale skin, headaches, shortness of breath, jaundice, dark urine, pale stool, splenomegaly (enlarged spleen), and bone deformities. Diagnosis is made through blood tests and genetic testing, and treatment involves blood transfusions, chelation therapy, and gene therapy.

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Prevalence & Risk factors

About 1.5% of the global population (80 to 90 million people) is estimated to be beta-thalassemia carriers. The prevalence of beta thalassemia varies depending on the population studied. The highest incidences of beta-thalassemia carriers are reported in Cyprus (14%) and Sardinia (12%). Beta thalassemia is relatively rare in other regions, such as the United States. It is often seen in places where malaria is common because it has been reported to have a protective effect against malaria caused by P. falciparum.^[1]

The risk factors that increase the likelihood of developing beta thalassemia include:

• Family history: Beta thalassemia is an inherited disorder, so having a family history of the condition increases the risk of developing it.
• Ethnicity: Beta thalassemia is more common in people of Mediterranean, African, Middle Eastern, and Southeast Asian descent.

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Genetics

Beta thalassemia is an autosomal recessive genetic disorder. It results from mutations in the HBB gene, which encodes the beta globin protein. Individuals with two mutated alleles (homozygous) display severe symptoms, while carriers (heterozygous) often exhibit no or mild effects. 

The severity of beta thalassemia varies depending on the specific mutations involved and their impact on beta globin production. Molecular diagnostics and carrier screening play crucial roles in identifying carriers and at-risk couples.^[2]

Autosomal recessive disorders arise when an individual acquires a defective gene from both parents. If someone inherits one functional gene and one affected gene associated with the disorder, they become carriers who usually have no symptoms.

When both parents are carriers, there is a 25% chance of both transmitting the faulty gene and having an affected offspring. The likelihood of having a child who, like the parents, is a carrier stands at 50%. There is a 25% possibility for a child to inherit normal genes from both parents. This applies equally to men and women.^[3]

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Pathophysiology

Red Blood Cells are the component of blood responsible for carrying oxygen. Hemoglobin is the protein inside these cells, allowing them to bind and carry oxygen. Hemoglobin has an organic protein component - the globin; and an inorganic part, an arrangement of 4 iron atoms that allows for the temporary binding of oxygen.^[1]

A mutation in hemoglobin results in a decreased capacity of red blood cells to carry oxygen, leading to disease development. Individuals with one affected allele are said to be carriers, and the disease manifests as beta thalassemia minor (the least severe form of Beta thalassemia). Those with both alleles mutated can manifest as beta thalassemia major or intermedia. 

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Signs & Symptoms 

The signs and symptoms of beta thalassemia greatly vary in severity. It depends on the specific mutations in the HBB gene.^[3]

We can distinguish between 3 main forms of beta thalassemia: 

• Beta thalassemia minor, also known as carrier state. One of the HBB genes has a mutation, but the other gene is normal. This results in a mild reduction in the production of beta-globin. It can be asymptomatic or can lead to mild anemia. Individuals with this type have a 50% chance of passing the mutation to their offspring. 
• Beta thalassemia intermedia. There are mutations in both HBB genes, but beta-globin production is not completely absent. This results in moderate to severe anemia that may require occasional blood transfusions and other treatments.
• Beta thalassemia major, also known as Cooley's anemia, has mutations in both HBB genes, resulting in little or no production of beta-globin. This leads to severe, life-threatening anemia that requires lifelong blood transfusions and other treatments. Without treatment, beta thalassemia major can lead to organ damage and early death.

Defective beta globin production damages your red blood cells and their subsequent removal from circulation. If you don't have enough red blood cells to carry oxygen to your body's tissues, you will develop anemia. It can present with symptoms like fatigue, dizziness, pale skin, headaches, shortness of breath, jaundice (yellow discoloration of skin, mucous membranes, and sclera), dark urine, and pale stool.
Furthermore, individuals suffering from beta thalassemia can have an enlarged spleen (splenomegaly) because too many blood cells are destroyed there. The abnormal production and destruction of red blood cells can cause bone marrow expansion and overstimulation, leading to bone deformities. 

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Diagnosis

Beta-thalassemia is usually diagnosed through a combination of blood tests and genetic testing. Blood tests can measure hemoglobin levels and other components in the blood and help determine whether a person has anemia. Genetic testing can identify mutations in the HBB gene that cause beta-thalassemia. Prenatal testing is also available for families with a history of beta-thalassemia.^[4,5]

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Therapy 

The treatment of beta thalassemia depends on the type and severity of the condition. ^[3,5]

Thalassemia major requires regular blood transfusions to replace the defective red blood cells. However, repeated blood transfusions can cause iron buildup in the body, leading to organ damage. To prevent this, people with thalassemia major often require chelation therapy, which involves taking medication to remove excess iron from the body. Sometimes, a bone marrow or cord blood transplant may be a possible cure for thalassemia major.

Thalassemia intermedia may not require regular blood transfusions, but people with this form of the disease may still need occasional transfusions to manage their symptoms. Iron chelation therapy may also be necessary in some cases.

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Prevention 

Since beta thalassemia is an inherited disorder, there is no way to prevent it from occurring in families with a history of the condition. However, genetic counseling can help couples with a family history of beta thalassemia understand their risk of having a child with the disease and explore prenatal diagnosis and treatment options.

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Prognosis

Beta thalassemia is a genetic blood disorder that can cause serious health problems if left untreated. However, with proper medical care and support, many people with beta-thalassemia can lead full and productive lives.

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