Thalassemia

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Basics

Description

  • 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

Epidemiology

  • α-Thalassemia:
    • Predominantly in Chinese subcontinent, Malaysia, Indochina, and Africa
    • African Americans
  • β-Thalassemia:
    • Mediterranean countries, Africa, India, Pakistan, Middle East, and China

Risk Factors

Genetics

  • α-Thalassemia
    • 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.
  • β-Thalassemia
    • 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).
GenotypeNameDegree of Anemia
α-Thalassemia
αα/αSilent carrierAsymptomatic
α–/α– or αα/–>–α-Thalassemia traitAsymptomatic
α–/– –α-Thalassemia intermedia, HbH diseaseModerate to severe
– –/– –α-Thalassemia majorHydrops fetalis
β-Thalassemia
β/β+ or β/β0β-Thalassemia traitAsymptomatic
β/β0 or β+/β+β-Thalassemia intermediaVariable, intermittent, or chronic transfusions
β0/β+ or β0/β0β-Thalassemia majorSevere, chronic transfusions

Pathophysiology

  • Decrease in either α- or β-globin synthesis leads to fewer completed α2β2 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).

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Basics

Description

  • 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

Epidemiology

  • α-Thalassemia:
    • Predominantly in Chinese subcontinent, Malaysia, Indochina, and Africa
    • African Americans
  • β-Thalassemia:
    • Mediterranean countries, Africa, India, Pakistan, Middle East, and China

Risk Factors

Genetics

  • α-Thalassemia
    • 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.
  • β-Thalassemia
    • 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).
GenotypeNameDegree of Anemia
α-Thalassemia
αα/αSilent carrierAsymptomatic
α–/α– or αα/–>–α-Thalassemia traitAsymptomatic
α–/– –α-Thalassemia intermedia, HbH diseaseModerate to severe
– –/– –α-Thalassemia majorHydrops fetalis
β-Thalassemia
β/β+ or β/β0β-Thalassemia traitAsymptomatic
β/β0 or β+/β+β-Thalassemia intermediaVariable, intermittent, or chronic transfusions
β0/β+ or β0/β0β-Thalassemia majorSevere, chronic transfusions

Pathophysiology

  • Decrease in either α- or β-globin synthesis leads to fewer completed α2β2 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).

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