Thalassemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Shyam Patel [3]
Overview
Thalassemia (British spelling, "thalassaemia") is an inherited autosomal recessive blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Reduced synthesis of one of the globin chains causes the formation of abnormal hemoglobin molecules, and this in turn causes the anemia which is the characteristic presenting symptom of the thalassemias.
Thalassemia is a quantitative problem of too few globins synthesized, whereas sickle-cell disease (a hemoglobinopathy) is a qualitative problem of synthesis of a non-functioning globin. Thalassemias usually result in under production of normal globin proteins, often through mutations in regulatory genes. Hemoglobinopathies imply structural abnormalities in the globin proteins themselves [1]. The two conditions may overlap, however, since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some thalassemias are hemoglobinopathies, but most are not. Either or both of these conditions may cause anemia.
Historical Perspective
Our knowledge about the origins of thalassemia date back to more than 6000 years ago. At that time, persons of Mediterranean descent began their migrations to other regions of the world, carrying gene variants that eventually gave rise to thalassemias. The expansion of empires led to further propagation of the defective globin genes throughout the world. It was soon noted that persons with thalassemia were relatively resistant to malaria, and further molecular studies were done to identify the underlying pathophysiology of thalassemias. The initial treatment approach to thalassemia was supportive care, especially red blood cell transfusions. In the recent years, bone marrow transplant and gene therapy have been exploited as possible treatments to treat thalassemias. These treatment strategies are still being explored.
Classification
The thalassemias are classified into two broad disease groups: alpha-thalassemia and beta-thalassemia. Alpha-thalassemia is characterized by a decrease in or defective production of alpha-globin chains. There are four major type of alpha-thalassemia, and each depends of on the number of alpha-globin alleles that are lost. These include the silent carrier state, alpha-thalassemia trait, HbH disease, and hydrops fetalis (Hb Barts). Beta-thalassemia is characterized by a decrease in or defective production of beta-globin chains. There are three major types of beta-thalassemia, and each depends on the degree of production of beta-globin chains. These include beta-thalassemia minor, beta-thalassemia intermedia, and beta-thalassemia major (Cooley's anemia). The beta-thalassemias can also be categorized by the degree of beta-globin chain production (B0 or B+ phenotypes).
Pathophysiology
The pathophysiology of alpha- and beta-thalassemia involves abnormal production of globin chains. Alpha- and beta-thalassemias are both monogenic disorders, meaning that defects in one gene result in the disease. The pathogenesis of thalassemias can involve a various of mutational events, such as deletions, insertions, or point mutations (substitutions). The altered genetic sequence results in a gene product (protein) that is nonfunctional or dysfunctional, such that the new globin chain cannot effective deliver oxygen to peripheral tissues. The number of alleles that are lost on each globin-cluster determines the severity of the disease. Regardless of the type of mutation, the thalassemias are inherited in a Mendelian autosomal recessive fashion.
Differentiating Thalassemia from Other Diseases
A variety of diseases can mimic thalassemia. These include sickle cell anemia, iron-deficiency anemia, hemolytic anemia, sideroblastic anemia, anemia of chronic disease, vitamin B12 deficiency, and erythropoietin deficiency. It is important to distinguish amongst these conditions, as each condition has different clinical consequences and treatment considerations.
Epidemiology and Demographics
Overall, thalassemia is a rare condition with a low incidence and prevalence in the United States. However, non-US countries have a higher incidence and prevalence. These include countries of the Mediterranean basis and Southeast Asia. The exact incidence and prevalence are unknown, but various estimates have been reported.