Chapter 15: The Thalassemias

DEFINITION

• Each of these disorders results from an inherited defect in the rate of synthesis of one or another of globin chains.

• Resultant imbalance of globin chain production may cause ineffective erythropoiesis, defective hemoglobin production, red cell hemoglobin precipitates, hemolysis, anemia of variable degree and propensity to iron overload.

ETIOLOGY AND PATHOGENESIS

Genetic Control and Synthesis of Hemoglobin

• Each hemoglobin (Hb) molecule consists of two separate pairs of identical globin chains.

• All normal human Hb molecules found in an adult have one pair of α-chains. The α-chains can combine with β-chains (α₂β₂), δ-chains (α₂δ₂), and γ-chains (α₂γ₂).

• Adult Hb is ~97% Hb A (α₂β₂), ~0.5% Hb F α2γ2, and ~2.5% Hb A₂ (α₂δ₂).

• In fetal life, Hb F (α₂γ₂) predominates. Position 136 of some γ-chains is occupied by glycine and in others by alanine. These are designated ^Gγ and ^Aγ, respectively. At birth Hb F is a mixture of α₂^Gγ₂ and α₂^Aγ₂ in a ratio of 3:1.

• In embryonic life, Hb Gower 1 is composed of dimers of zeta (ζ) and epsilon (ε) globins (ζ₂ε₂). Hb Gower 2 (α₂ε₂) and Hb Portland (ζ₂γ₂) are only present before the 8th week of intrauterine life.

• During fetal life, globin gene expression switches occur from ζ- to α- and from ∈- to γ-chain production, followed by β- and δ-chain production at perinatal life.

Globin Gene Clusters

• α-Gene cluster (chromosome 16) consists of one functional ζ gene and two α genes (α₂ and α₁).

• Exons of the two α-globin genes have identical coding sequences; however, they differ in second intron.

• Production of α₂ mRNA exceeds that of α₁, by factor of 1.5 to 3.

• β-Gene cluster (chromosome 11) consists of one functional ∈ gene, a ^Gγ gene, an ^Aγ gene, a pseudo β gene, a δ gene, and a β gene.

• Flanking regions contain conserved sequences essential for gene expression.

Regulation of Globin Gene Clusters

• Primary transcript is a large mRNA precursor, with both intron and exon sequences, which is extensively processed in the nucleus to yield the final mRNA.

• Expression of the globin genes is regulated by complex control mechanisms.

Developmental Changes in Globin Gene Expression

• β-Globin produced at low levels beginning at 8 to 10 weeks of fetal life increases considerably at about 36 weeks gestation.

• γ-Globin produced at high levels early starts to decline at ~36 weeks.

• At birth, β-globin and γ-globin production are approximately equal.

• By age 1 year, γ-globin ...