Sickle Cell Disease

Incidence

Sickle hemoglobin is the most common abnormal hemoglobin found in the United States (approximately 8% of the African-American population has sickle cell trait). The expected incidence of sickle cell disease (SCD) at birth is 1 in 625.

Genetics

1. Sickle cell disease is transmitted as an incomplete autosomal dominant trait.

2. Homozygotes (two abnormal genes) do not synthesize hemoglobin A (HbA); red cells contain 90-100% hemoglobin S (HbS).

3. Heterozygotes (one abnormal gene) have red cells containing 20-40% HbS.

4. HbS arises as a result of spontaneous mutation and deletion of the P-globin gene on chromosome 11, which results in selective advantage against Plasmodium falciparum malaria in carriers (balanced polymorphism).

5. a-Thalassemia (frequency of 1-3% in African Americans) may be co-inherited with sickle cell trait or disease. Individuals who have both a-thalassemia and sickle cell anemia are less anemic than those who have sickle cell anemia alone. However, a-thalassemia trait does not appear to prevent frequency or severity of vaso-occlusive complications.

Results of DNA polymorphism linked to the Ps gene suggest that it arose from three independent mutations in tropical Africa:

1. Benin-Central West African haplotype (the most common haplotype)

2. Senegal-African West Coast haplotype

3. Bantu-Central African Republic (CAR) haplotype

The Benin type is also found in Ibadan, Algeria, Sicily, Turkey, Greece, Yemen, and southwest Saudi Arabia. In Caribbean and North American patients of African heritage with SCD, 50-70% of chromosomes are Benin, 15-30% are Bantu-CAR, and 5-15% are Senegal. The Benin and Senegalese patients have higher levels of fetal hemoglobin (HbF) and fewer dense cells compared with Bantu-CAR patients. Patients with Senegal haplotype have the least severe disease, whereas patients with Bantu-CAR haplotype have most severe disease.

Pathophysiology

Figure 7-4 depicts the pathophysiology of sickle cell disease.

A single amino acid substitution (valine for glutamic acid) occurs in the P-polypeptide chain. This simple alteration has the following consequences:

1. Hemoglobin S has a higher net electrical charge than that of hemoglobin A and hence a different electrophoretic mobility.

2. Hemoglobin S in the reduced form (deoxygenated) is less soluble than hemoglobin A. The molecules form rod-like tactoids; these in turn distort the red cell, which takes on the sickle form (Figure 7-4).

DNA mutation

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