This disorder can be described as an intrinsic normocytic hemolytic anemia, meaning that this is a disease where blood cells are abnormally broken down and the defect is due to the red blood cell itself. In the case of sickle-cell disease, there is abnormal hemoglobin production, leading to abnormally shaped cells.
Sickle cell disorder is caused by a single point mutation in the β-globin chain of hemoglobin, causing glutamic acid to be replaced by valine. HbS (hemoglobin S) is formed from two normal α-chains binding with two mutant β-chains. Patients can be heterozygous (one abnormal allele of hemoglobin beta gene) or homozygous (more severe, because of both abnormal alleles).
Sickle-cell conditions have an autosomal recessive pattern of inheritance. The types of hemoglobin a person makes in the red blood cells depend on what hemoglobin genes are inherited from her or his parents. If one parent has sickle-cell anaemia (SS) and the other has sickle-cell trait then there is a 50% chance of a child having sickle-cell disease and a 50% chance of a child having sickle-cell trait. When both parents have sickle-cell trait a child has a 25% chance of sickle-cell disease, 25% will not carry any sickle cell alleles, and 50% will have the heterozygous condition.
8% of African americans carry HbS trait (heterozygotes, who have 1 abnormal hemoglobin beta allele).
In sickle-cell disease, low O2 tension or dehydration leads to red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells cannot return to normal shape when normal O2 tension is restored. Thus, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.
Due to the presence of HbF (fetal hemoglobin), which does not include β-chains, but rather γ-chains, newborns are typically asymptomatic. Symptoms occur at 6-9 months of age as HbF production decreases and HbS is created as adult hemoglobin.
Patients who are heterozygotes for HbS, or those with sickle-cell trait, only have 1 abnormal β-hemoglobin allele. Thus, they produce both HbS and normal hemoglobin. Patients display more resistance to falciparum malarial infections and show less severe symptoms.
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