Spherocytosis

Hereditary spherocytosis (MIM 182900) Mutations in the genes encoding spectrin or other structural proteins in the red cell membrane... 

Hereditary spherocytosis Deficiencies in the amount or in the structure of a or p spectrin, ankyrin, band 3 or band 4.1... 

Adapted from Lux DE, Becker PS Disorders of the red cell membrane skeleton hereditary spherocytosis and hereditary elliptocytosis. Chapter 95 in The Metabolic Basis of Inherited Disease, 6th ed. Scriver CR et al (editors). McGraw-Hill, 1989. 

Abnormalities in the Amount or Structure of Spectrin Cause Hereditary Spherocytosis Elliptocytosis... 

Hereditary spherocytosis is a genetic disease, transmitted as an autosomal dominant, that affects about 1 5000 North Americans. It is characterized by the presence of spherocytes (spherical red blood cells, with a low sur-face-to-volume ratio) in the peripheral blood, by a hemolytic anemia, and by splenomegaly. The spherocytes are not as deformable as are normal red blood cells, and they are subject to destruction in the spleen, thus greatly shortening their Ufe in the circulation. Hereditary spherocytosis is curable by splenectomy because the spherocytes can persist in the circulation if the spleen is absent. 

One cause of hereditary spherocytosis (Figure 52-5) is a deficiency in the amount of spectrin or abnormalities of its structure, so that it no longer tightly binds the other proteins with which it normally interacts. This weakens the membrane and leads to the spherocytic shape. Abnormalities of ankyrin and of bands 3 and 4.1 are involved in other cases. 

Hereditary elliptocytosis is a genetic disorder that is similar to hereditary spherocytosis except that affected red blood cells assume an elliptic, disk-hke shape, recognizable by microscopy. It is also due to abnormalities in spectrin some cases reflect abnormahties of band 4.1 or of glycophorin C. 

Causes within the membrane include abnormahties of proteins. The most important conditions are hereditary spherocytosis and hereditary eUiptocytosis, principally caused by abnormalities in the amount or structure of spectrin (see above). 

Deficiency of spectrin results in hereditary spherocytosis, another important cause of hemolytic anemia. 

Hemolytic anemia results from decreased RBC survival time due to destruction in the spleen or circulation. The most common etiologies are RBC membrane defects (e.g., hereditary spherocytosis), altered Hb solubility or stability (e.g., sickle cell anemia [see Chap. 34] and thalassemias), and changes in intracellular metabolism (e.g., glucose-6-phosphate dehydrogenase deficiency). Some drugs cause direct oxidative damage to RBCs (see Appendix 3). 

Lymphocyte chromosomal breaks Increased red-cell spherocytosis after in vitro radiation... 

Increased red-oell spherocytosis Mouse, rat. after in vitro radiation rabbit, man... 

What is the function of the membrane skeleton There is a group of hereditary diseases including spherocytosis in which erythrocytes do not maintain their biconcave disc shape but become spherical or have other abnormal shapes and are extremely fragile.269 272 Causes of spherocytosis include defective formation of spectrin tetramers and defective association of spectrin with ankyrin or the band 4.1 protein.265 273 Thus, the principal functions of these proteins in erythrocytes may be to strengthen the membrane and to preserve the characteristic shape of erythrocytes during their 120-day lifetime in the bloodstream. In other cells the spectrins are able to interact with microtubules, which are absent from erythrocytes, and to microtubule-associated proteins of the cytoskeleton (Chapter 7, Section F).270 In nerve terminals a protein similar to erythrocyte protein 4.1 may be involved in transmitter release.274 The cytoskeleton is also actively involved in transmembrane signaling. 

Related proteins occur in other tissues.488 The 911-residue band 3 protein consists of two distinct parts of nearly equal size. The N-terminal portion is attached to the membrane skeleton (Fig. 8-16). The C-terminal part, which is embedded in the membrane, is thought to form 14 transmembrane helices and to contain the ion exchange channel or channels.4893 As previously mentioned, defects in the N-terminal portion cause spherocytosis. The mutation Arg 589 His in the C-terminal half causes renal tubular acidosis in which the kidneys do not adequately remove acids from the body.238 489 Band 3 proteins can also exchange phosphate, sulfate, and phosphoenolpyruvate for Cl or bicarbonate. 

Hematological Disorders. Blood related diseases include hereditary spherocytosis, pyruvate kinase deficiency, glucose-6-phosphate dehydrogenase deficiency, and hemoglobinopathies, such as thalassemias. 

Hereditary spherocytosis (HS) comprises a group of inherited hemolytic anemias characterized by chronic hemolysis with a broad spectrum of severity (Hassoun et al, 1997). The principal cellular defect is the loss of erythrocyte surface area relative to the intracellular volume, although increased osmotic frailty is also a factor. A distinctive spherical red blood cell (RBC) morphology is observed in sufferers of HS and splenic destruction of these abnormal erythrocytes is the primary cause of the hemolysis experienced (Delaunay, 1995 Palek and Jarolim, 1993). 

Agre, P., Casella, J. F., Zinkham, W. H., McMillan, C., and Bennett, V. (1985). Partial deficiency of erythrocyte spectrin in hereditary spherocytosis. Nature 314, 380-383. 

Becker, P. S., Tse, W. T., Lux, S. E., and Forget, B. G. (1993). Beta spectrin kissimmee A spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1./. Clin. Invest. 92, 612-616. 

Eber, S. W., Armbrust, R., and Schroter, W. (1990). Variable clinical severity of hereditary spherocytosis Relation to erythrocytic spectrin concentration, osmotic fragility, and autohemolysis./. Pediatr. 117, 409-416. 

Gallagher, P. G., and Forget, B. G. (1998). Hematologically important mutations Spectrin and ankyrin variants in hereditary spherocytosis. Blood Cells Mol. Dis. 24, 539-543. 

Hassoun, H., and Palek, J. (1996). Hereditary spherocytosis A review of the clinical and molecular aspects of the disease. Blood Rev. 10, 129-147. 

Hassoun, H., Vassiliadis, J. N., Murray, J., Yi, S. J., Hanspal, M., Ware, R. E., Winter, S. S., Chiou, S. S., and Palek, J. (1995). Molecular basis of spectrin deficiency in beta spectrin Durham. A deletion within beta spectrin adjacent to the ankyrin-binding site precludes spectrin attachment to the membrane in hereditary spherocytosis. / Clin. Invest. 96, 2623-2629. 

Sawides, P., Shalev, O., John, K. M., and Lux, S. E. (1993). Combined spectrin and ankyrin deficiency is common in autosomal dominant hereditary spherocytosis. Blood 82, 2953-2960. 

Waugh, R. E., and Agre, P. (1988). Reductions of erythrocyte membrane viscoelastic coefficients reflect spectrin deficiencies in hereditary spherocytosis. J. Clin. Invest. 81, 133-141. 

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