THALASSEMIAS

• Thalassemias are a diverse group of inherited disorders caused by genetic mutations affecting the globin chain component of the hemoglobin (Hb) tetramer
• Thalassemia first described by Cooley and Lee in four children with anemia, splenomegaly, mild hepatomegaly, and mongoloid facies


  1925
• Whipple and Bradford published a paper outlining detailed autopsy studies of children who died of this disorder


  1932
• Thalassemia


  Greek for "great sea" anemia
• Thalassemias


  Named according to the chain with reduced or absent synthesis
• Mutations affecting the a- or ẞ-globin gene are most clinically significant because Hb A (α2ß2) is the major adult hemoglobin
• The decreased or absent synthesis of one of the chains not only leads to a decreased production of hemoglobin, but also results in an imbalance in the a/ẞ chain ratio
• The unaffected gene continues to produce globin chains at normal levels, and the accumulation of the unpaired normal chains damages red blood cells (RBCs) or their precursors, resulting in their premature destruction
• Across the world, an estimated 56,000 infants are conceived or born with a clinically significant thalassemia each year, with more than half requiring regular transfusions
• It is estimated that 5% of the world's population is a carrier of an α-thalassemia mutation and 1.5% is a carrier of a ẞ-thalassemia mutation
• The geographic location of the thalassemia belt coincides with areas in which malaria is prevalent
• A 2012 meta-analysis showed a decreased risk of severe malaria in a-thalassemia, both in heterozygotes and homozygotes
• The normal hemoglobin molecule is a tetramer of two a-like chains (a or () and two ẞ-like chains (ẞ, y, d, or e)
• The a-like globin gene cluster is located on chromosome 16, whereas the B-like globin gene cluster is on chromosome 11
• The a-like globin gene cluster contains three functional genes: HBZ (-globin), HBA1 (a₁-globin), and HBA2 (a2-globin)
• The B-like globin gene cluster contains five functional genes: HBE (e-globin), HBG2 (Gy-globin), HBG1 (Ay-globin), HBD (8-globin), and HBB (ẞ-globin)
• By 6 months of age and through adult life, Hb A (α2ẞ2) is the predominant hemoglobin
• The gene for the d chain is activated shortly before birth, but owing to its weak promoter, only produces a relatively small amount of 8 chain, resulting in a low level of Hb A₂(α282) throughout life
• Normal hemoglobins in adults

  • Hb A (α2ẞ2) - 95%-100%
  • Hb A₂ (α282) - 0%-3.5%
  • Hb F (α2Y2) - 0%-2%
• The genotype for normal ẞ chain synthesis is designated B/B
• The normal genotype for a-globin genes is designated aa/aa
• Categories of thalassemia


  • ẞ-thalassemias
  • a-thalassemias
• ẞ°


  Designation for the various mutations in the ẞ-globin gene in which no ẞ chains are produced
• ẞ+


  Designation for the various mutations in the ẞ-globin gene that result in a partial deficiency of ẞ chains (ranging from 5% to 30% of normal) and a decrease in production of Hb A
• ẞ silent


  Designation for mutations in the B-globin gene that lead to minimal reductions in ẞ chain production and are associated with mild or silent clinical states
• 8ẞ°


  Designation for mutations in the d- or ẞ-globin genes in which no d or ẞ chains are produced
• SẞLepore


  Designation for a fusion of the 8- and ẞ-globin genes that produces Hb Lepore
• a


  Designation for a deletion of either the α₁- or the α₂-globin gene on chromosome 16, resulting in decreased production of a chains from that chromosome
• a°


  Designation for a deletion of both the a₁- and α2-globin genes on chromosome 16, resulting in no production of a chains from that chromosome
• Genetic defects causing thalassemia

  • Single nucleotide (or point) mutations
  • Small insertions or deletions
  • Large deletions
• Mechanisms by which genetic defects interfere with globin chain production

  1. Reduced or absent transcription of mRNA

  2. mRNA processing errors

  3. Translation errors
• Types of genetic defects that cause reduced or absent production of a particular globin chain

  • Reduced or absent transcription of mRNA
  • mRNA processing errors
  • Translation errors
  • Deletion of one or more globin genes
• Thalassemia syndromes


  • Reduction or lack of synthesis of one or more globin chains
• a/ẞ chain imbalance


  Determines the clinical severity of thalassemia
• Mechanisms in ẞ-thalassemia


  1. Unpaired, excess a chains precipitate in developing erythroid precursors

  2. Apoptosis is triggered

  3. Damaged and apoptotic erythroid precursors are phagocytized and destroyed

  4. Iron accumulation and inflammatory cytokines contribute to apoptosis

  5. Ineffective erythropoiesis

  6. Extravascular hemolysis
• In ẞ-thalassemia major


  • Profound anemia stimulates increase in erythropoietin production
  • Massive but ineffective erythroid hyperplasia occurs
• Radiographic abnormalities in ẞ-thalassemia major

  • Lacy or lucent appearance of long bones
  • "Hair on end" appearance of skull
• Complications in ẞ-thalassemia major

  • Growth retardation and absence of sexual maturity
  • Cardiomyopathy, fibrosis and cirrhosis of the liver, and dysfunction of exocrine glands
• Mechanisms of iron accumulation in ẞ-thalassemia major

  1. Regular RBC transfusions

  2. Elevated EPO level promotes upregulation and secretion of erythroferrone

  3. Low hepcidin level allows increased iron absorption by intestinal enterocytes
• In non-transfusion-dependent ẞ-thalassemia, increased erythroferrone levels may explain the pathologic decrease in hepcidin and the development of iron overload