Thalassemia classification
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2] Neel Patel, M.B.B.S[3]
Overview
The thalassemias are categorized 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 types of alpha-thalassemia, and each depends 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).
Classification
The thalassemias are classified according to which chain of the hemoglobin molecule is affected.
Alpha-thalassemia
Alpha-thalassemias are caused by decreased production of alpha-globin chains from chromosome 16. Alpha-thalassemia is a monogenic disorder, meaning that one gene abnormality causes one disease.[1] This is an autosomal recessive disorder with clinical manifestations that can be mild or severe, depending on the degree of alpha-globin loss. Mild clinical symptoms occur if there is a loss of one alpha-globin chain, and severe symptoms can occur if there is a loss of four alpha-globin chains. The hemoglobin molecules are that reduced in alpha-thalassemias include:
- major adult hemoglobin (HbA) (consisting of tetramers of alpha2-beta2)
- minor adult hemoglobin (HbA2) (consisting of tetramers of alpha2-delta2)
- fetal hemoglobin (HbF) (consisting of tetramers of alpha2-gamma2)
Loss of 1 alpha chain (silent carrier)
This is known as the silent carrier state. These patients are asymptomatic, since there are three remaining functional alpha-globin chains.
Loss of 2 alpha chains (trait)
This is known as alpha-thalassemia trait. These patients are generally asymptomatic, since there are two remaining functional alpha-globin chains.
Loss of 3 alpha chains (HbH)
This condition occurs when alpha-globin chain synthesis is reduced to 25% or less.[2] This is also know as hemoglobin H (HbH). HbH consists of tetramers of beta chains (beta-4).[2] These beta-globin chain tetramers form because of insufficient alpha-globin chain synthesis. Symptoms typically include severe hemolytic anemia, but not death. This condition is less severe than Hb Barts but more severe than alpha-thalassemia silent carrier or trait.
Loss of 4 alpha chains (Hb Barts)
Complete loss of alpha-globin chain production results in a severe, clinically incapacitating anemia with production of 4 gamma-globin chains as a tetramer. The clinical syndrome is hydrops fetalis. The tetramer of 4 gamma-globin chains (gamma-4) is also known as hemoglobin Barts (Hb Barts). This condition is not compatible with life. There can be severe intrauterine anemia. These patients typically die in utero or shortly after birth.
Hemoglobin Constant Spring
This is a variant alpha-hemoglobinopathy but is not formally classified as a thalassemia. Hemoglobin Constant Spring is characterized by a point mutation (substitution) in the alpha2-globin chain at the translation termination codon. This is a nondeletional alpha-thalassemia. The point mutation converts TAA to CAA, resulting in a prolonged peptide chain of 172 amino acids instead of the usual 141 amino acids. The peptide product is an elongated and unstable alpha-globin chain. This hemoglobinopathy is found in persons of Chinese and Southeast Asian descent.[3]
Beta-thalassemia
Beta-thalassemias are caused by decreased production of beta-globin chains from chromosome 11. Beta-thalassemia is a monogenic disorder, meaning that one gene abnormality causes one disease, similar to alpha-thalassemia.[1] This is an autosomal recessive disorder with clinical manifestations that can be mild or severe, depending on the degree of beta-globin loss. Mild clinical symptoms occur if there is a loss of one beta-globin chain, and severe symptoms can occur if there is loss of two beta-globin chains.
Beta-thalassemia minor
This is the most mild form of beta-thalassemia, which involves nearly intact beta-globin production. It is associated the B+ thalassemia phenotype.
Beta-thalassemia intermedia
This is a beta-thalassemia of moderate severity, which involves some loss of beta-globin production.
Beta-thalassemia major (Cooley's anemia)
This is the most severe form of beta-thalassemia, which involves loss of all beta-globin production. It is associated the B0 thalassemia phenotype.
Beta0 thalassemia (B0 thalassemia)
Patients with B0 thalassemia have absent beta-globin production. They have high red blood cell counts despite anemia. Red blood cells in B0 thalassemia heterozygotes are hypochromic and microcytic, meaning that they have loss of central pallor and small size, respectively. This disease is characterized by unbalanced or unequal globin chain synthesis and increased HbA2 (which consists of two alpha-globin chains and two delta-globin chains).[4] B0 thalassemia is commonly seen in beta-thalassemia major, or Cooley's anemia.
Beta+ thalassemia (B+ thalassemia)
Patients with B+ thalassemia have some beta-globin production. They have high red blood cell counts despite anemia. Red blood cells in B+ thalassemia are hypochromic and microcytic also. This disease is characterized by unbalanced or unequal globin chain synthesis and increased HbA2 (which consists of two alpha-globin chains and two delta-globin chains).[4] The difference between patients with B0 thalassemia and B+ thalassemia is that patients with B+ thalassemia produce some functional beta-globin and thus synthesize some functional red blood cells. B+ thalassemia can be found in patients with beta-thalassemia intermedia or beta-thalassemia minor.
Hemoglobin E (HbE)
This is a beta-globin variant that is found in high prevalence in certain Asian countries.[5] It is characterized by a point mutation in beta-globin at codon 26, in which GAG is converted to AAG, converting glutamic acid to lysine. This amino acid substitution results in altered messenger RNA processing. Given the high prevalence of beta-thalassemia in Asian countries, some patients can have HbBE disease, in which one allele harbors a beta-globin defect and the other harbors the beta-globin variant.[5] The rate of production of hemoglobin for patients with HbE disease is slightly decreased, so the thalassemia is mild. In patients with HbE, this hemoglobin variant constitutes 25-30% of the total hemoglobin. HbE has mild sensitivity to oxidative stress. This hemoglobin variant is unstable at high temperatures, so patients with HbE may experience hemolysis in the heat.
Hemoglobin E/beta-thalassemia (HbBE)
- Mutation: Given the high prevalence of beta-thalassemia in Asian countries and the relative abundance of HbE amongst Asians, some patients can have HbBE disease, in which one allele harbors a beta-globin defect and the other harbors the beta-globin variant.[5] This point mutation results in a cryptic splice site and abnormal processing of messenger RNA. This results in reduced rate of synthesis of the beta-globin chain, which impairs red blood cell production and leads to apopotosis, oxidative damage, and anemia.
- Geography: The areas of highest prevalance include India, Laos, Cambodia, Bangladesh, Thailand. The incidence of HbE in Thailand is about 3000 per year.[6] The prevalence is about 100,000. This is a compound heterozygote condition and results in an intermediate severity of thalassemia. HbE can also be inherited with certain forms of alpha-thalassemia. It accounts for nearly 50% of all major beta-thalassemias.[6]
Hemoglobin C (HbC)
This is a hemoglobin variant characterized by a point mutation at the 6th codon of the beta-globin chain. It results in conversion of glutamic acid to lysine. Note that this is distinct from hemoglobin E, in which a similar amino acid substitution occurs in codon 26.
Hemoglobin AE Barts
This is a rare hemoglobinopathy in which there is co-existence of hemoglobin A, hemoglobin E, hemoglobin Barts (complete loss of alpha chains).
References
- ↑ 1.0 1.1 Harteveld CL, Higgs DR (2010). "Alpha-thalassaemia". Orphanet J Rare Dis. 5: 13. doi:10.1186/1750-1172-5-13. PMC 2887799. PMID 20507641.
- ↑ 2.0 2.1 Higgs DR (2013). "The molecular basis of α-thalassemia". Cold Spring Harb Perspect Med. 3 (1): a011718. doi:10.1101/cshperspect.a011718. PMC 3530043. PMID 23284078.
- ↑ Jomoui W, Fucharoen G, Sanchaisuriya K, Nguyen VH, Fucharoen S (2015). "Hemoglobin Constant Spring among Southeast Asian Populations: Haplotypic Heterogeneities and Phylogenetic Analysis". PLoS One. 10 (12): e0145230. doi:10.1371/journal.pone.0145230. PMC 4686174. PMID 26683994.
- ↑ 4.0 4.1 Cao A, Kan YW (2013). "The prevention of thalassemia". Cold Spring Harb Perspect Med. 3 (2): a011775. doi:10.1101/cshperspect.a011775. PMC 3552345. PMID 23378598.
- ↑ 5.0 5.1 5.2 Fucharoen S, Weatherall DJ (2012). "The hemoglobin E thalassemias". Cold Spring Harb Perspect Med. 2 (8). doi:10.1101/cshperspect.a011734. PMC 3405827. PMID 22908199.
- ↑ 6.0 6.1 Olivieri NF, Pakbaz Z, Vichinsky E (2011). "Hb E/beta-thalassaemia: a common & clinically diverse disorder". Indian J Med Res. 134: 522–31. PMC 3237252. PMID 22089616.