Chicago Center for Jewish Genetics Disorders - Sephardic Disorders: Beta-thalassemia

Sephardi Disorders

Gene: Beta-thalassemia is caused by mutations in the beta-globin gene, which is located at 11p15.15. It encodes the beta chain of hemoglobin A, which carries oxygen in the blood.

Mutations and testing: There are more than 200 mutations known but certain mutations tend to occur in a population-specific manner. Most individuals are compound heterozygotes and the particular combination results in varying severity of disease. Homozygosity or compound heterozygosity for two "severe" alleles results in severe disease, while two "mild" or "silent" beta-chain mutations, may produce only mild disease. Compound heterozygosity for "mild" or "silent" and "severe" beta-chain mutations results in a phenotype ranging from mild to severe. Molecular testing can be done to determine the specific disease-causing mutation and this is done predominately to differentiate between "mild" and "severe" alleles. Hemoglobin electrophoresis or HPLC should also been done for the detection of beta-thalassemia and other hemoglobinopathies that may interact with beta-thalassemia.

Traits: Hemoglobin carries the oxygen in the blood to cells located in other parts of the body. Hemoglobin synthesis begins at 3 weeks gestation during embryonic development. As the fetus develops and then is born, the individual chains making up the hemoglobin change. As a fetus, the main hemoglobin is HbF, which is made up on two alpha chains and two gamma chains. Adult hemoglobin A (HbA) is made up of 2 alpha chains and 2 beta chains. By 3 months of age, HbA production equals HbF production and by 12 months the latter accounts for less than 5% of all hemoglobin. In beta-thalassemia there is a decrease in the amount of beta-chains available to form HbA and this results in precipitation of the excess alpha chains. This precipitation leads to the damage and eventual death of red blood cells causing anemia. There are three main types according the severity of the defect:

Thalassemia major (homozygous): This occurs when there is complete absence of beta-globin chains and marked excess of alpha chains. Onset is often before 2 years of age and symptoms are severe microcytic anemia and hepatosplenomegaly. Skeletal changes can also occur due to expansion of the bone marrow to compensate for ineffective erythropoiesis. Survival of patients is more than 30 years with early transfusion and chelation therapy.
Thalassemia intermedia: This occurs when there is some beta-chain production, resulting in less severe symptoms. Clinical features are pallor, jaundice, cholelithiasis (gallstones), heptatosplenomegaly, moderate to severe skeletal changes, leg ulcers, a tendency to develop osteopenia and osteoporosis, and thrombotic complications. Transfusions are often needed.
Thalassemia minor (heterozygous): Patients are asymptomatic but might have mild microcytic anemia demonstrated on blood tests.

Treatment: Transfusion therapy is necessary for thalassemia major to control the anemia. This is performed in conjunction with chelation therapy in order to remove excess iron. Excess iron can result in damage to the liver, lung, heart, pancreas, and endocrine glands. Hydroxyurea has been tried to increased production of gamma-globin chains, which are part of HbF, another hemoglobin in the body. Splenectomy may be necessary. Treatment of thalassemia intermedia is based upon symptoms.

Modifying factors: The severity of symptoms in thalassemia major may be lessened by coinheritance of alpha-globin mutations associated with alpha-thalassemia. This can reduce the alpha-globin gene output and therefore lessen the imbalance in the alpha chain to beta chain ratio. Coinheritance of factors able to sustain a continuous production of gamma-globin chains (HbF) in adult life, called hereditary persistence of fetal hemoglobin (HPFH), may reduce the alpha chain imbalance. This results in a milder phenotype in someone with beta-thalassemia.

Beta-Thalassemia and Malaria: Beta-thalassemia may provide a selective advantage in endemic areas such as Sub-Saharan Africa, Southern Asia, and the Middle East by possibly providing protection against malaria. Beta-thalassemia heterozygotes may have mild microcytic anemia which may prevent the falciparum malaria to reach maturity. This has been seen for G6PD Deficiency.

Reviewed by Dr. Joel Charrow, Children's Memorial Hospital.
1/03

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This page last updated on January 10, 2003.