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Sickle Cell Anemia - HBB

Clinical Features

Sickle cell anemia usually manifests between the 3rd and 4th month of life by pallor, jaundice and is characterized by two symptom complexes:

• The abnormal hemoglobin molecules tend to aggregate especially under hypoxic conditions which gives rise to the characteristic sickle form of erythrocytes. This impairs microcirculation and eventually results in occlusive vessel disease. There may be attacks of thrombotic crises with severe pain and swelling of the affected parts (hand-foot-syndrome, bones and joints, abdominal crises, lung infarction, CNS crises and kidney damage) which often follow a dramatic course.

• Erythrocyte flexibility is reduced due to the sickle form and red blood cells are thus sequestrated in liver and spleen (chronic-hemolytic anemia). A large blood volume may be sequestrated in the spleen leading to shock-like conditions. Relapsing infarctions of the spleen lead to functional asplenia and severe septicemia.
  Hb-electrophoresis in patients reveals extremely high levels of HbS. As compensation, HbF may be formed which alleviates the symptoms.

Genetic Information

Sickle cell anemia is inherited as an autosomal recessive condition. It is caused by a mutation in the HBB (hemoglobin-beta) gene on chromosome 11p15.5. The point mutation in codon 6 results in an amino acid exchange from glutamic acid to valine. In most cases, there is homozygosity for this point mutation. A compound-heterozygosity with the known mutation and a different amino acid exchange at the same position (Glu->Lys) usually gives rise to milder symptoms (so-called HbSC disease). Combinations of heterozygous HbS mutations with additional mutations in the beta globin gene or with other hemoglobinopathies show a more variable symptomatic spectrum. Heterozygosity for HbS causes no disability.

Prevalence

Heterozygous carriers:
High regional variability; up to 1:3 in some African populations

Diagnostic