Epidemiology

• α‐thalassemia is more common in the Far East with up to 40% of the regional population being carriers, and less commonly in India, Kuwait, the Middle East, Greece, Italy, and Northern Europe.
• About 3% of the world’s population (150 million people) carry β-thalassemia genes. β‐Thalassemia is more common in the Mediterranean region. They are particularly prevalent in inhabitants of Italy and Greece.
• Most appear to have been selected because the carrier state affords some protection against malaria. RBCs with common hemoglobinopathies (eg, α- and β-thalassemias, HbS, HbC, HbE) and enzyme (glucose-6-phosphate dehydrogenase) defects have shown a reduced parasite invasion/growth and an increased susceptibility to phagocytosis of the infected RBC as a malaria-protective effect.

Pathobiology

Hemoglobin Synthesis

The globin gene clusters on chromosomes 16 and 11. In embryonic, fetal and adult life different genes are activated or suppressed. The different globin chains are synthesized independently and then combine with each other to produce the different hemoglobins. The γ gene may have two sequences, which code for either a glutamic acid or alanine residue at position 136 (Gγ or Aγ , respectively). The locus control region (LCR) is a genetic regulatory element, situated upstream of the β‐globin cluster, that controls genetic activity by opening up the chromatin to allow transcription factors to bind. A similar region applies to α‐globin synthesis.

• The genes for the globin chains occur in two clusters: ε, γ, δ and β on chromosome 11 and ζ and α on chromosome 16.
• In the embryo and fetus, Gower 1, Portland, Gower 2 and fetal Hb dominate at different stages.
• The α‐chain gene is duplicated and both α genes (α1 and α2) on each chromosome are active.
  • The α complex is arranged in the order of expression during development: 5′ζ2 … α2-α1.
  • The embryonic ζ gene shows 58% homology with the α gene coding region.
  • The level of transcription of the two α genes differs: The α2 gene expresses two to three times more α-globin than α1. This would imply that Hb is made up of approximately 35% α2 gene and 15% α1 globin structural variants.
  • Individuals most often have four α-globin genes, but as a result of unequal genetic exchange, some people may exhibit five or six α genes, while being phenotypically normal.
• The β‐globin gene is expressed at a low level in early fetal life, but the main switch to adult hemoglobin occurs 3–6 months after birth when synthesis of the γ chain is replaced by β chains.
  • BCL11A is a major transcriptional regulator of the switch. Other nuclear transcriptional factors are involved.
  • The methylation state of the gene (expressed genes are hypomethylated, non‐expressed hypermethylated), the state of the chromosome packaging and enhancer sequences all play a part in determining whether a particular gene will be transcribed.
• Two types of γ chain occur, Gγ and Aγ , which differ by a glycine or alanine amino acid at position 136 in the polypeptide chain.

(b) Synthesis of individual globin chains in prenatal and postnatal life.

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The ratio of α:β globin chain synthesis (y axis) depending on the number of functioning a and b chain genes (x axis).

**α-**Thalassemia

The α-globin genes are embedded within two highly homologous regions extending for about 4 kb, whose homology has been maintained by gene conversion and unequal crossover events. Three homologous subsegments (X, Y, and Z) separated by nonhomologous elements have been defined. Reciprocal recombination between Z boxes (3.7 kb apart) and between X boxes (4.2 kb apart) gives rise to chromosomes with only one α-gene. These common α-thalassemia determinants are referred to as −α 3.7 kb rightward deletion or −α 4.2 kb leftward deletions, respectively.

• α-Thalassemia is most frequently caused by deletional mutations that involve one or both α-globin genes.