Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Spherocytosis [D58.0]

OMIM numbers: 182900, 612641 (ANK1), 612653, 109270 (SLC4A1), 182870 (SPTB), 612690, 177070 (EPB42), 270970, 182860 (SPTA1)

Dipl.-Biol. Birgit Busse, Dipl.-Biol. Wolfgang Rupprecht

Scientific Background

Hereditary spherocytosis (HS) is the main cause of congenital hemolytic anemia among Caucasians. The prevalence is approx. 1:2,000 to 1:5,000. The molecular cause is a defect of erythrocyte membrane proteins, which play a key role in the stabilization and organization of the plasma membrane. A defect in this network leads to loss of shape of the erythrocytes (spherocytes) and to increased membrane permeability, increased glycolysis and elevated ATP turnover. The spherocytes are removed from the blood circulation at an early stage by the spleen.

Hereditary spherocytosis is a clinically, biochemically and genetically heterogeneous disease. Main signs and symptoms are normocytic hemolytic anemia, icterus and splenomegaly. Gallstones are frequently seen. The signs and symptoms may vary strongly and can range from an asymptomatic form to a severe life-threatening anemia which requires treatment with transfusions and splenectomy.

Inheritance can be both autosomal dominant and recessive; approx. 2/3 of all cases, however, follow a dominant pattern. In 65% of all Northern European patients, mutations are found in the ANK1 gene, which encodes the protein ankyrin-1. Frameshift or stop mutations usually cause a dominant phenotype; missense or promoter mutations cause a recessive phenotype. Mutations in the SLC4A1 gene are considered to be the second most frequent cause. These mutations lead to a defect of the band 3 protein. Inheritance is autosomal dominant. Moreover, in approx. 15-30% of all cases, mutations are described in the β-spectrin, which is encoded by the SPTB gene. In rare cases, the α-spectrin or the protein 4.2 is affected with a proportion of less than 5% each.