Hemoglobin sickle cell disease

Manning JM et aJ Normal and abnormal protein subunit interactions in hemoglobins.] Biol Chem 1998 273 19359-Mario N, Baudin B, Giboudeau J Qualitative and quantitative analysis of hemoglobin variants by capillary isoelectric focusing. J Chromatogr B Biomed Sci Appl 1998 706 123-Reed W, Vichinsky EP New considerations in the treatment of sickle cell disease. Annu Rev Med 1998 49 46l. 

O Sickle cell disease is an inherited disorder caused by a defect in the gene for hemoglobin. Patients may have one defective gene (sickle cell trait) or two defective genes (sickle cell disease). 

FIGURE 65-1. Sickle gene inheritance scheme for both parents with sickle cell trait (SCT). A, normal hemoglobin S, sickle hemoglobin. Possibilities with each pregnancy 25% normal (AA) 50% SCT (AS) 25% sickle cell anemia (SS). (From Chan CYJ, Moore R. Sickle cell disease. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy A Pathophysiologic Approach. 6th ed. New York McGraw-Hill 2005 1856.)... 

Sickle cell disease is caused by a mutation that results in the substitution of a valine residue for a glutamate residue in the sixth position of the hemoglobin P-chain. This results from the substitution of a T for an A in the glutamate codon. When (1) DNA from a patient... 

Restriction analysis can be used to detect sickle cell disease prenatally, since the DNA of all cells, including amniotic cells, carries the mutant DNA. It is much more difficult to obtain fetal blood for the analysis of the mutant hemoglobin A P-chain. Furthermore, fetal blood is composed mostly of fetal hemoglobin, sinee-hemoglobin A is made later in development. 

The most common abnormal hemoglobin in the United States is hemoglobin S (HbS). Two genes for HbS result in sickle cell disease (SCD) or sickle cell anemia, which occurs in 0.3% of African Americans. One gene for HbS results in sickle cell trait, which occurs in 8% of African Americans. Hemoglobin C, another abnormality, occurs in 2% to 3% of African Americans. 

A. N Gladwin, M. T., Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease, Nature Med. 8 (2002), p. 1383-1389... 

S. H., Increasing fetal hemoglobin in sickle cell disease comparisons of 5-azacytidine (subcutaneous or oral) with hydroxyurea, Trans. Assoc. Am. Physicians 97 (1984), p. 140-145... 

L3. Lathem, W., and Jensen, W., Plasma hemoglobin-binding capacity in sickle cell disease. Blood 14, 1047 (1959). 

In the majority of patients with sickle cell disease, anemia is not the major problem the anemia is generally well compensated even though such individuals have a chronically low hematocrit (20-30%), a low serum hemoglobin level (7-10 g/dL), and an elevated reticulocyte count. Instead, the primary problem is that deoxygenated HbS chains form polymeric structures that dramatically change erythrocyte shape, reduce deformability, and elicit membrane permeability changes that further promote hemoglobin polymerization. Abnormal erythrocytes... 

The diagnosis of sickle cell disease is based on the identification of the hemoglobin type found... 

A dominant theme in the treatment of sickle cell disease is the manipulation of the hemoglobin switch from fetal to adult hemoglobin. If the switch did not occur at all or if the y-globin gene did not completely switch to P-globin... 

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