Unstable Hemoglobinopathies

Unstable Hemoglobinopathies

 

Hemoglobinopathies are rare, inherited disorders caused by mutations of the globin genes.

Epidemiology

  • Incidence – rare
  • Age – neonatal; usually not in the first few months (protected by fetal hemoglobin)

Genetics

  • More than 30 mutations exist
  • Inherited as autosomal dominant disorders, although spontaneous mutations occur

Pathophysiology

  • Unstable hemoglobins exhibit altered solubility due to oxidation of amino acid residues in globin chains
    • Leads to weakened binding of heme to globin preventing formation of intact hemoglobin tetramer
    • Only tetramer can remain dissolved in circulating red blood cells (RBCs)
      • Mutants cannot remain dissolved
      • Leads to hemoglobin precipitation
    • Heinz body is precipitate of undissolved components of globin chains and heme
      • Attach to RBC membranes and trigger spleen to further damage RBCs
      • End result is premature destruction of RBCs with hemolysis and eventual anemia

Clinical Presentation

  • Congenital Heinz body hemolytic anemia
  • Jaundice, anemia, dark urine, leg ulcers, bilirubin gallstones
  • Neonatal syndromes
    • Hemoglobin Poole and Hemoglobin Hasharon
    • Neonatal hemolysis – jaundice, anemia
    • Resolves with aging as adult hemoglobin replaces fetal hemoglobin

Diagnosis

  • Laboratory testing
    • Heinz bodies variably present on peripheral blood smear
      • Provocative testing using isopropanol instability test will unmask precipitation and make diagnosis easier
    • Hemoglobin electrophoresis may show an abnormal band of precipitated heme and globin
      • Some mutants not detectable by electrophoresis or are too unstable

See Also