The human β-globin gene cluster is located on chromsome 11 and includes the epislon (ε: embryonic) gene, the gamma A and gamma G (Aγ; Gγ: fetal) genes, and the delta and beta (δ and β: adult) genes. The adult β-globin gene is specifically locate at 11p15.5 and is composed of 3 exons that encode a 147 amino acid protein.
A large number of mutations have been identified leading to decreased or absent production of β-globin chains resulting in the β-thalassemias. The β-thalassemias are inherited with an autosomal recessive pattern. In the most severe situation mutations in both the maternal and paternal β-globin genes leads to loss of normal amounts of β-globin protein. At the level of the β-globin proteins the β-thalassemias are characterized by whether or not there is partial or complete defect in protein production. A complete lack of protein is denoted as β0-thalassemia (beta-zero-thalassemia). If mutation(s) allows production of a small amount of functional β-globin then the disorder is denoted as β+-thalassemia (beta-plus-thalassemia). Clinically the β-thalassemias can be divided into three categories:
Thalassemia major patients require frequent blood transfusions for survival. Both β0- and β+-thalassemias are referred to as thalassemia major, also called Cooley anemia after Dr. Thomas Cooley who first described the disorder.
Thalassemia intermedia patients exhibit intermediate levels of severity. The term thalassemia intermedia is used to designate individuals with significant anemia and who are symptomatic but unlike thalassemia major do not require transfusions. This syndrome results in individuals where both β-globin genes express reduced amounts of protein or where one gene makes none and the other makes a mildly reduced amount. A person who is a compound heterozygote with α-thalassemia and β+-thalassemia will also manifest as thalassemia intermedia.
Thalassemia minor patients are heterozygous for β-thalassemia. Afflicted individuals harbor one normal β-globin gene and one that harbors a mutation leading to production of reduced or no β-globin. Individuals that do not make any functional β-globin protein from 1 gene are termed β0 heterozygotes. If β-globin production is reduced at one locus the individuals are termed β+ heterozygotes. Thalassemia minor individuals are generally asymptomatic.
The primary cause of the α-thalassemias is deletion, whereas, for β-thalassemias the mutations are more subtle. Over 170 different mutations have been identified resulting in the β-thalassemias. These mutations include gene deletions, point mutations in the promoter, mutations in the coding region leading to defective initiation, insertions and deletions resulting in frameshifts and nonsense mutations, point mutations in the polyadenylation signal, and an array of mutations leading to splicing abnormalities.
Whereas, thalassemia major may result from the homozygous inheritance of a β-thalassemia mutation it is more common that an individual inherits two different β-thalssemias. This latter situation is referred to as a compound heterozygosity. At birth most thalassemia major infants are asymptomatic. However, because fetal hemoglobin (HbF) production declines following birth symptoms of severe anemia will begin to present. If left untreated these children will show a marked retardation in growth rate. As a consequence of the anemia the bone marrow dramatically increases its' effort at blood production. The cortex of the bone becomes thinned leading to pathologic fracturing and distortion of the bones in the face and skull. Progressive hepatosplenomegaly is a constant clinical finding as the liver and spleen act as additional sites of blood production. The heptosplenomegaly leads to leukopenia (decreased white blood cell count) and thrombocytopenia (low platelet count). Recurrent infections are a frequent complication in thalassemia major and are the leading cause of morbidity and mortality in this disease. Frequent blood transfusions are required to maintain a hemoglobin level of 9 to 11g/dl. However, in the long term these transfusions lead to the accumulation of iron in the organs, particularly the heart, liver and pancreas. Organ failure ensues with death in the teens to early twenties. Iron chelation therapies appear to improve the outlook for β-thalassemia major patients but this requires continuous infusion of the chelating agent.
Thalassemia intermedia is a term used to describe thalassemia patients with anemia and splenomegaly but without the clinical severity of thalassemia major patients. In fact, this syndrome encompasses a range of clinical symptoms from the major form at the severe end to asymptomatic/symptomless. The diagnostic criteria for intermedia is a late presentation and the ability to maintain hemoglobin levels above 6g/dl without transfusion. At the extreme end of the spectrum patients will present with symptoms between 2 and 6 years of age. At the other end of the spectrum are patients who do not present with symptoms until adulthood.
Measurements for serum hemoglobin content, red cell hemoglobin content (mean corpuscular hemoglobin, MCH), and red cell volume (mean corpuscular volume, MCV) are all highly diagnostic for various forms of β-thalassemia major and intermedia. Individuals with β-thalassemia major or intermedia have MCV values that are almost always lower than those for individuals with α-thalassemia. The average MCV value for β-thalassemia patients is on the order of 60 ± 3.5fl (N: 82–98fl). The average MCH value in β-thalassemia is on the order of 19.7 ± 1.3pg (N: 26–34pg). The average hemoglobin content in the blood in β-thalassemia is 6–7g/dL (N: 12–16g/dL).