Hereditary spherocytosis pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The defects in hereditary spherocytosis lie in the cell membrane. The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizental alpha & beta spectrin molecules form heterodimers with linkage to vertical elements including ankyrin, proteins 4.1 & 4.2 and band 3 (transmembrane protein). The shorter the lifespan of red blood cells, the worse the clinical effects. Spectrin protein is a tetramer composed of alpha & beta dimers, its deficiency is most frequently seen in hereditary spherocytosis. Spectrin deficiency can result from impaired synthesis of spectrin or from qualitative or quantitative defects in other proteins that integrate proteins into red blood cells. Ankyrin is the principal binding site for spectrin on red blood cell membrane, its deficiency leading to decreased incorporation of spectrin, leading to proportional decrease in spectrin content as well despite normal synthesis of spectrin. Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis and is considerably greater in older red blood cells. Protein 4.2 (Pallidin) deficiency leads to abnormal red blood cell morphology including spherocytes, elliptocytes or sphero-ovalocytes, it is relatively common in japan. Red blood cell antibodies may also have a pathogenic role in red blood cell opsonization and removal by spleen.

• The defects in hereditary spherocytosis lie in the cell membrane.^[1]
• The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizontal alpha and beta spectrin molecules form heterodimers with linkage to vertical elements- ankyrin, proteins 4.1 and 4.2 and band 3 (a transmembrane protein).
• Different genes code for each of these proteins, therefore hereditary spherocytosis is a heterogenous disorder that can result from a defect in any one of these proteins.
• The destabilization of membrane leads to both abnormal morphology and reduced red cell life span.
• The shorter the lifespan of red blood cells, the worse the clinical effects.
• The genetic defect and clinical severity tend to be fairly constant within a given family, but between families varies from mild asymptomatic hemolysis to severe continuous anemia with jaundice.
• The four RBC membrane protein abnormalities recognized in hereditary spherocytosis include; spectrin deficiency alone, combined spectrin & ankyrin deficiency, band 3 deficiency and protein 4.2 deficiency.
• Spectrin deficiency
  • Spectrin protein is a tetramer composed of alpha and beta dimers.^[2][3]
  • The most frequent defect in hereditary spherocytosis is spectrin deficiency.
  • Mutations of alpha spectrin are associated with recessive forms of hereditary spherocytosis and beta spectrin mutations occur in autosomal dominant forms of hereditary spherocytosis.
  • Spectrin deficiency can result from impaired synthesis of spectrin or from quantitative or qualitative defects in other proteins that integrate spectrin into the red cell membrane.
  • Approximately 50% of patients with severe recessive hereditary spherocytosis have a point mutation at the codon (969) resulting in amino acid substitution (alanine/aspartic acid) at the corresponding site in apha spectrin protein leading to defective binding of spectrin to protein 4.1.
• Akyrin deficiency
  • Ankyrin is the principal binding site for spectrin on the red blood cell membrane.
  • Ankyrin gene is located on chromosome 8, therefore translocation of chromosome 8 or deletion of short arm of chromosome 8 can lead to hereditary spherocytosis.
  • Ankyrin deficiency leads to decreased incorporation of spectrin, leading to a proportional decrease in spectrin content as well despite the normal synthesis of spectrin.
• Band 3 deficiency
  • Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis.
  • Band 3 deficiency is considerably greater in older RBCs due to unstable nature of band 3 protein.
• Protein 4.2 (Pallidin) Deficiency
  • Protein 4.2 deficiency leads to abnormal RBC morphology including spherocytes, elliptocytes or sphero-ovalocytes.
  • Its deficiency is relatively common in japan.
  • A point mutation causing complete absence of protein 4.2 is associated with typical hereditary spherocytosis phenotype.
• Red Blood Cell Antibodies
  • Zaninoni et all found RBC antibodies in 61% of patients with hereditary spherocytosis using a mitogen stimulated direct antiglobulin test.^[4]
  • They concluded that the more evident hemolytic pattern in patients with RBC autoantibodies suggests that these antibodies have a pathogenic role in RBC opsonization and removal by spleen.

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