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INTRODUCTION

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Normal hemoglobin (Hb) structure and developmental changes in production are detailed in Chapter 425. Thousands of variants in the α-, β-, minor, and fetal globin genes have been described, some of which are associated with tremendous morbidity or mortality. However, most hemoglobin variants have no clinically significant effect on hemoglobin or red blood cell (RBC) function. A continuously updated listing of Hb variants, many of which are named after the town or geographic regions where they were identified (eg, Hb Köln), is provided in the HbVar database at http://globin.cse.psu.edu/hbvar/menu.html.

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Hemoglobin disorders can be classified as qualitative or quantitative. Qualitative abnormalities arise from mutations that change the amino acid sequence of the globin, thereby producing structural and functional changes; they are known as hemoglobinopathies. Qualitative disorders in Hb can be manifest as (1) decreased solubility, (2) instability, (3) altered oxygen affinity, and (4) altered oxidation state of the heme-coordinated iron. Quantitative hemoglobin disorders result from the decreased and imbalanced production of generally structurally normal globins. For example, if β-globin production is diminished by a mutation, there will be a relative excess of α-globins. Such imbalanced production of α- and β-globins damages RBCs and their precursors in the bone marrow. These quantitative hemoglobin disorders are called thalassemias. Although some thalassemias are also hemoglobinopathies, most hemoglobin variants are neither a hemoglobinopathy or a thalassemia. Both qualitative and quantitative disorders of hemoglobin can be subdivided by the particular globin that is affected; for example, there can be α-thalassemias and β-hemoglobinopathies.

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This chapter provides a review of several of the common qualitative hemoglobin disorders and is followed by a review of the thalassemias.

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SICKLE CELL DISEASE

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Sickle cell disease (SCD) is the name for a group of related disorders caused by sickle hemoglobin (Hb S). Hb S is a qualitatively abnormal hemoglobin caused by a point mutation of the β-globin gene. The sixth codon of the normal β-globin gene, GAG, codes for glutamic acid. In Hb S, the adenine nucleotide is replaced by thymidine, producing GTG, which is a codon for valine. Glutamic acid is actually the seventh amino acid in the β-globin peptide but was designated the sixth because the invariant initial methionine residue was historically not numbered; this numbering convention has been retained for Hb S, which was the first molecular lesion identified in a disease gene. The glutamine-to-valine substitution replaces a hydrophilic glutamic acid with a hydrophobic valine, permitting abnormal hydrophobic interactions between adjacent deoxyhemoglobin molecules, which decreases the solubility of Hb S in the deoxygenated state. Thus, as sickled RBCs traverse the circulation, cycling through oxygenated and deoxygenated states, Hb S repeatedly forms rigid polymers that damage the RBC membrane, causing a hemolytic anemia and, ultimately, the systemic manifestations of SCD.

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EPIDEMIOLOGY

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Sickle cell trait, the heterozygous or carrier state for the Hb S mutation, protects against severe ...

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