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- Thalassemia syndromes are hereditary microcytic anemias that result from mutations that quantitatively reduce globin synthesis.
- Normal hemoglobin (Hb) is a tetramer of 2 α and 2 β chains:
- α-Thalassemia: reduced or absent α-globin production
- β-Thalassemia: reduced or absent β-globin production
- Predominantly in Chinese subcontinent, Malaysia, Indochina, and Africa
- African Americans
- Mediterranean countries, Africa, India, Pakistan, Middle East, and China
- Normally, there are four α-globin genes, two on each chromosome 16.
- Most mutations in α-thalassemia are large deletions.
- Deletions may be in trans conformation (one deletion on each chromosome, common in African Americans) or cis conformation (two genes deleted on same chromosome, common in Asians).
- Hb Constant Spring is an α-globin gene mutation caused by a point mutation that reduces or eliminates production of α-globin, leading to a more severe phenotype.
- The four α-thalassemia syndromes reflect the inheritance of molecular defects affecting the output of 1, 2, 3, or 4 α genes.
- Normally, there are two β-globin genes, one on each chromosome 11.
- Most mutations in β-thalassemia are point mutations.
- Many mutations abolish the expression completely (β0), whereas others variably decrease quantitative expression (β+).
- Heterozygous state for β-globin mutation produces β-thalassemia trait.
- Homozygous state produces β-thalassemia major or β-thalassemia intermedia.
- Note: Rare dominant β-thalassemia mutations exist, causing ineffective erythropoiesis with a single mutation (due to creation of unstable β-globin variants).
|Genotype||Name||Degree of Anemia|
|αα/α –||Silent carrier||Asymptomatic|
|α–/α– or αα/–>–||α-Thalassemia trait||Asymptomatic|
|α–/– –||α-Thalassemia intermedia, HbH disease||Moderate to severe|
|– –/– –||α-Thalassemia major||Hydrops fetalis|
|β/β+ or β/β0||β-Thalassemia trait||Asymptomatic|
|β/β0 or β+/β+||β-Thalassemia intermedia||Variable, intermittent, or chronic transfusions|
|β0/β+ or β0/β0||β-Thalassemia major||Severe, chronic transfusions|
- Decrease in either α- or β-globin synthesis leads to fewer completed α2–β2 tetramers produced per RBC, which results in a decrease in intracellular Hb and microcytosis.
- Unpaired globin chains precipitate, resulting in apoptosis of red cell precursors (ineffective erythropoiesis) and damage to the RBC membrane leading to hemolysis.
- Ineffective erythropoiesis causes hepatosplenomegaly and osseous changes.
- The erythrocyte’s lifespan is shortened by hemolysis and splenic trapping.
- Degree of anemia varies depending on the specific gene defect.
- Chronic transfusion therapy and, to a lesser degree, increased absorption of dietary iron in thalassemia major lead to iron accumulation.
- Increased absorption of dietary iron and intermittent transfusions in thalassemia intermedia lead to iron accumulation.
- Iron overload leads to cardiac arrhythmias and congestive heart failure (CHF) that can be fatal, liver inflammation and fibrosis, and endocrinopathies (e.g., diabetes mellitus, hypothyroidism, gonadal failure, osteoporosis).