Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Beta Thalassemia [D56.1]

OMIM numbers: 613985, 141900 (HBB)

Dipl.-Biol. Birgit Busse, Dipl.-Biol. Wolfgang Rupprecht

Scientific Background

Beta thalassemia is a heterogeneous group of diseases with autosomal recessive inheritance caused by a reduced synthesis of a structurally normal β-globin. The homozygous type is also called thalassemia major - the heterozygous type is called thalassemia minor. Variant forms occur associated with combined heterozygosity of hemoglobin variants such as sickle cell hemoglobin or Hb Lepore. Thalassemia minor is mainly characterized by a mild microcytic, hypochromic anemia that does not cause any significant clinical symptoms. The degree of severity of the intermediate type of beta thalassemia (thalassemia intermedia) lies between thalassemia minor and major. Symptoms of thalassemia major, also called Cooley anemia, usually already occur in the first few months of life when HbF is replaced by HbA0. The symptoms of affected children include failure to thrive, hepatosplenomegaly, icterus, severe microcytic hypochromic anemia with a striking erythrocyte morphology. If left untreated the increased but ineffective erythropoesis leads to characteristic skeletal changes (especially at the skull and facial bones) due to a widening of the medullary cavity. Mutations in the β-globin gene (HBB) leading to a reduced or absent synthesis of β-globin chains are the molecular cause of beta thalassemia. This results in an unbalanced synthesis of globin chains and thus to an increased amount of free α-globin chains which precipitate rapidly due to their instability. This leads already in the bone marrow to premature hemolysis of erythrocytes and their precursors. The symptomatic treatment of thalassemia major consists of regular blood transfusions. An additional therapy with iron absorption inhibitors is indicated to avoid an iron overload which bears the risk of hemosiderosis. Bone marrow transplantation is currently considered the only curative treatment approach.

The hemoglobin molecule consists of 4 globin chains - a heterotetramer made up of two types of chains (HbA0: α2β2, HbA2: α2δ2, HbF: α2γ2). Diagnosis is mostly performed by hemoglobin electrophoresis (elevated HbA2, depending on the case HbF as well). Confirmation is done by the molecular genetic detection of 1 or 2 mutations in the HBB gene. It is estimated that approx. 3% of the global population are carriers of beta thalassemia trait. However, the prevalence varies substantially among different ethnicities. A very high prevalence can be found in Mediterranean countries, parts of Asia, the Middle East, and in West Africa.

Crystal structure of hemoglobin (Tame and Vallone 2000, PDB entry 1A3N, www.pdb.org)