Thalassemia classification
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]
Overview
Classification
The thalassemias are classified according to which chain of the hemoglobin molecule is affected (see hemoglobin for a description of the chains). In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected.
Alpha-thalassemia
Alpha-thalassemias are caused by decreased production of alpha-globin chains from chromosome 16. 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 loss of one alpha-globin chain, and severe symptoms can occur if there is loss of 4 alpha-globin chains. Alpha-thalassemia is a monogenic disorder, meaning that one gene abnormality causes one disease.[1] The hemoglobin molecules are that reduced in alpha-thalassemias include the major adult hemoglobin (HbA) (consisting of tetramers of alpha2-beta2), the minor adult hemoglobin (HbA2) (consisting of tetramers of alpha2-delta2), and fetal hemoglobin (HbF) (consisting of tetramers of alpha2-gamma2).
Loss of 1 alpha chains
This is known as the silent carrier state. These patients are asymptomatic, since there are 3 remaining functional alpha-globin chains.
Loss of 2 alpha chains
This is known as alpha-thalassemia trait. These patients are generally asymptomatic, since there are 2 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 consistes of tetramers of beta chains (beta-4).[2] These beta-glbin 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.
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 nor 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
Beta0 thalassemia (B0 thalassemia)
Heterozygotes that have B0 thalassemia have high [[red blood cell] counts. Red blood cells in beta-thalassemia 0 heterozygotes are hypochromic and microcytic. 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]
Beta+ thalassemia (B+ thalassemia)
Heterozygotes that have B+ thalassemia have high [[red blood cell] counts. Red blood cells in B+ thalassemia are hypochromic and microcytic. 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]
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
- ↑ 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.