What is the role of genetics in the etiology of beta thalassemia?

Updated: Dec 19, 2018
  • Author: Pooja Advani, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Mutations in globin genes cause thalassemias. Beta thalassemia affects one or both of the beta-globin genes. More than 200 beta-globin gene mutations have been identified in these patients; this underlies the wide genotypic and phenotypic variability of the disease. [2]  (Alpha thalassemia affects the alpha-globin gene[s].) These mutations, by causing impaired synthesis of the beta-globin protein component of Hb, result in anemia. [3, 4]

Beta thalassemia is inherited as an autosomal recessive disorder. The defect can be a complete absence of the beta-globin protein (ie, beta-zero thalassemia) or a severely reduced synthesis of the beta-globin protein (ie, beta-plus thalassemia). (See the image below.)

Peripheral smear in beta-zero thalassemia minor sh Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.

Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.The genetic defect usually is a missense or nonsense mutation in the beta-globin gene, although occasional defects due to gene deletions of the beta-globin gene and surrounding regions also have been reported.

In beta thalassemia minor (ie, beta thalassemia trait or heterozygous carrier-type), one of the beta-globin genes is defective, resulting in an approximately 50% decrease in the synthesis of the beta-globin protein.

In beta thalassemia major (ie, homozygous beta thalassemia), the production of the beta-globin chains is severely impaired because both beta-globin genes are mutated. The severe imbalance of globin chain synthesis (alpha >> beta) results in ineffective erythropoiesis and severe microcytic hypochromic anemia. (See the image below.)

Peripheral smear from a patient with beta-zero tha Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.

Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent. The excess unpaired alpha-globin chains aggregate to form precipitates that damage red cell membranes, resulting in intravascular hemolysis. Premature destruction of erythroid precursors results in intramedullary death and ineffective erythropoiesis. The profound anemia typically is associated with erythroid hyperplasia and extramedullary hematopoiesis.

Although beta thalassemia is caused by a genetic mutation in the beta-globin gene (which is located on chromosome 11), many additional factors influence the clinical manifestations of the disease. That is, the same mutations may have different clinical manifestations in different patients. The factors below are known to influence the clinical phenotype.


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