Hereditary spherocytosis and related disorders.

A number of abnormalities in cellular physiology have been observed in hereditary spherocytes, including alterations in shape, membrane cation permeability and deformability, intracellular metabolism and tendency for splenic entrapment. Many observations have been observed only in a subset of patients with HS and may studies have not been confirmed. Therefore, it is likely that there is heterogeneity with regard to the specific molecular cause of the disease. The major research problem has been to determine primary molecular defects in HS. Much evidence supports a molecular defect in the erythrocyte membrane skeleton and three abnormalities involving spectrin have been demonstrated to be directly related to HS. First, spectrin deficiency has been shown in autosomal recessive spherocytosis in mouse mutants and partial deficiency observed in all human patients with HS. Second, a specific functional defect in spectrin purified from the red cells of some kindreds with autosomal dominant HS has been identified: lack of binding capacity for protein 4.1. Third, a less well characterized functional abnormality has been described in which spectrin binds more tightly to the erythrocyte membrane. These defects may, by an unidentified mechanism, contribute to the spheroidal shape and haemolytic disease ameliorated by splenectomy. More definitive studies are necessary in order to determine the origins of HS. Such studies require: Use of appropriate controls for splenectomy and young red cell age, Tracing a defect through affected family members, Verifying that a defect corresponds to the appropriate heredity pattern, for example that a heterozygote for an autosomal dominant defect had 50% abnormal protein, Differentiating the effects of splenic or circulatory conditioning from the primary red cell defects, Verifying that the defect is present in the intact cell and is not secondary to experimental manipulations, Distinguishing an unrelated, linked polymorphism from the primary mutation responsible for the disorder. Finally, the pathophysiology of the disease will have to be explained on the basis of the primary molecular defect, as well as the mechanism of all secondary physiological changes in the hereditary spherocyte.