| More than 600 mutations in the genes encoding the α- and β-globin polypeptides have been documented. As with most mutational events, the majority of these lead to few, if any, clinical problems. There are, however, several hundred mutations that give rise to abnormal Hb and pathologic phenotypes. Hb mutants or hemoglobinopathies are usually named after the location (hospital, city, or geographical region) in which the abnormal protein was first identified. They are classified according to the type of structural change and altered function and the resulting clinical characteristics (Table 4.1 and 4.2). While many of these mutants have predictable phenotypes, there are others that are surprisingly pleiotropic in their impact on multiple properties of the Hb molecule. With few exceptions, Hb variants are inherited as autosomal recessive traits. Occasionally, double heterozygotes are identified, e.g., HbSC (see Fig. 4.8).
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| page 47 |  | | page 48 |
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Table 4-1.
Classification and examples of hemoglobinopathies. |
| Body_ID: None |
| Classification and examples of hemoglobinopathies |
| Body_ID: T004001.50 |
| Classification | Common name mutation | | Biochemical change | Clinical consequences |
| Body_ID: T004001.100 |
| abnormal solubility | HbC (common) | Glu6 β→Lys | cellular crystallization of oxygenated protein; increased fragility | mild anemia; splenomegaly (enlarged spleen) |
| Body_ID: T004001.150 |
| decreased O2 affinity | Hb Titusville (rare) | Asp94 α→Asn | heterodimer interface altered to stabilize T-state | mild cyanosis (blue-purple skin coloration from deoxygenated blood) |
| Body_ID: T004001.200 |
| increased O2 affinity | Hb Helsinki (rare) | Lys82 β→Met | reduced binding of 2,3-BPG in T-state | mild polycythemia (increased erythrocyte count) |
| Body_ID: T004001.250 |
| ferric heme (methemoglobin) | HbM Boston (rare) | His58 α→Tyr | altered heme pocket (loss of distal His) and decreased Bohr effect | cyanosis of skin and mucous membranes |
| Body_ID: T004001.300 |
| unstable protein | Hb Gun Hill (rare) | Δβ91-95 | misfolding caused by loss of Leu in heme pocket and shorter helix | formation of Heinz bodies (inclusions of denatured Hb); jaundice (yellow coloration of integument and sclera); pigmented urine |
| Body_ID: T004001.350 |
| abnormal synthesis | Hb Constant Spring (rare) | ter142 α→Gln | loss of termination codon; decreased mRNA stability | α-thalassemia (hemolytic anemia,splenomegaly, and jaundice) |
| Body_ID: T004001.400 |
|
| Body_ID: T004001.450 |
Hemoglobinopathies are usually classified according to the most prominent change to the protein's structure, function, or regulation. Initial identification of a mutation often involves electrophoretic or chromatographic analysis, as shown in Figure 4.8 for HbSC, a double heterozygous genotype associated with a sickle cell disease-like phenotype.
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|
Table 4-2.
Complete blood count. |
| Body_ID: None |
| Complete blood count (CBC) |
| Body_ID: T004002.50 |
| Parameter | Sample | Normal value* |
| Body_ID: T004002.100 |
| white blood cell count,WBC | 6.82 ×103/mm3 | 4.5-11.0 ×103 |
| Body_ID: T004002.150 |
| red cell count, RBC | 4.78 ×106/mm3 | 4.1-5.1 ×103 (F) |
| Body_ID: T004002.200 |
| | | 4.5-5.3 ×103 (M) |
| Body_ID: T004002.250 |
| hemoglobin, Hb | 9.9 g/dL | 12.0-16.0 (F) |
| Body_ID: T004002.300 |
| | | 13.0-18.0 (M) |
| Body_ID: T004002.350 |
| hematocrit, HCT | 33.4% | 36-46 (F) |
| Body_ID: T004002.400 |
| | | 37-49 (M) |
| Body_ID: T004002.450 |
| mean corpuscular volume, MCV | 71.9 fL | 78-100 |
| Body_ID: T004002.500 |
| mean corpuscular hemoglobin, MCH | 21.3 pg/cell | 25-35 |
| Body_ID: T004002.550 |
| mean corpuscular hemoglobin concentration, MCHC | 29.6 g/dL | 31-37 |
| Body_ID: T004002.600 |
| red cell distribution width, RDW | 17.7% | 11.5-14.5 |
| Body_ID: T004002.650 |
| platelet count, PLT | 274 ×103/mm3 | 150-400 ×103 |
| Body_ID: T004002.700 |
| mean platelet volume,MPV | 8.6 fL | 6.4-11.0 |
| Body_ID: T004002.750 |
|
| Body_ID: T004002.800 |
*A Kratz and KB Lewandrowski (1998) Normal reference laboratory values. New Engl J Med 339:1063-1072
Automated laboratory evaluation of blood provides invaluable information for the diagnosis and monitoring of health problems. The complete blood count (CBC) includes cell counts of erythrocytes, white cells, and platelets and quantitative indices of the red cells (MCV, MCH, MCHC, and RDW). The results describe the hematopoietic status of the bone marrow and the presence of anemia and its possible cause. Data presented are characteristic of an individual with iron deficiency anemia: low HGB, low MCV (microcytosis), and low MCH (hypochromia). mm3 =μL.
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| A complete blood count (CBC) provides information on blood cell populations and their characteristics. Data are obtained from whole blood samples by automated hematology analysis. Some instruments also provide leukocyte differentials, reticulocyte count, and red cell morphology. A typical printout of the results for one individual and the range for normals is shown in Table 4.2. |
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