Mutations in the globin genes that alter the protein composition but not necessarily the amount of expression are referred to as qualitative mutations. Of the mutations leading to qualitative alterations in hemoglobin, the missense mutation in the β-globin gene that causes sickle cell anemia is the most common. The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The change converts a glutamic acid codon (GAG) to a valine codon (GTG). The form of hemoglobin in persons with sickle cell anemia is referred to as HbS. The nomenclature for normal adult hemoglobin protein is HbA1. Adult red blood cells also carry another minor form of adult hemoglobin (about 2% of the total) identified as HbA2. The HbA1 heterotetramer is composed of two α-globin peptides and two β-globin peptides. The HbA2 heterotetramer is composed of two α-globin peptides and two δ-globin peptides. The human β-globin gene cluster contains several genes whose 5' to 3' orientation on chromosome 11 reflects the ontogeny of their expression from embryonic globin [episilon (ε) gene], to fetal β-globin [gammaG (γG) and γA genes], to adult β-globin [weakly the delta (δ) gene followed by the β gene]. The β-globin gene (HBB) is located at 11p15.5 and is composed of 3 exons that encode a 147 amino acid protein.
The underlying problem in sickle cell anemia is that the valine for glutamic acid substitution results in hemoglobin tetramers that aggregate into arrays upon deoxygenation in the tissues. This aggregation leads to deformation of the red blood cell into a sickle-like shape making it relatively inflexible and unable to traverse the capillary beds. This structural alteration in the red blood cell can easily be seen under light microscopy and is the source of the name of this disease. Repeated cycles of oxygenation and deoxygenation lead to irreversible sickling.
Sickle cell anemia is an autosomal recessive disorder. This means that in order for full disease symptoms to manifest in an individual they must carry two copies (homozygous genotype = SS) of the HbS gene. However, individuals who are heterozygous (genotype = AS) have what is referred to as sickle cell trait, a phenotypically dominant trait. Although AS individuals are clinically normal their red blood cells can sickle under very low oxygen pressure, e.g. when at high altitudes in airplanes with reduced cabin pressure. Because of this phenomenon, AS individuals exhibit phenotypic dominance yet are recessive genotypically.
Sickle cell anemia is characterized by persistent episodes of hemolytic anemia and the occurrence of acute episodes referred to as sickling crises. The sickling red cells result in clogging of the fine capillary beds. In addition, due to these recurrent vasculo-occlusive episodes there are a series of complications. Because bones are particularly affected by the reduced blood flow, frequent and severe bone pain results. This is the typical symptom during a sickle cell crisis. Long term, the recurrent clogging of the capillary beds leads to damage to the internal organs, in particular the kidneys, heart and lungs. The continual destruction of the sickled red blood cells leads to chronic anemia and episodes of hyperbilirubinemia.
Sickle cell anemia usually presents in infancy although milder cases will only manifest later in life. The hallmark presentations are failure to thrive and repeated infections and repeated attacks of painful hand-foot syndrome, termed dactylitis. This symptom is characterized by sudden onset of a painful swelling of the back (dorsum) of the hands and feet. Presenting infants will be pale with slight jaundice (icterus) visible in the sclera of the eyes and the spleen will be palpable. The clinical course of sickle cell anemia is variable even within the afflicted individuals of the same sibship.
Children with sickle cell anemia have an increased susceptibility to infections due to Streptococcus pneumonia, Salmonella, and Hemophilus influenza. The increased propensity to infection results in impaired splenic function that resembles infections in children who have had their spleens removed for other reasons. Pneumococcal pneumonia and septicemia are the most devastating consequences of sickle cell anemia. Septicemia and shock is a common cause of death particularly in infants and during childhood.