HbSmutation

The HbS mutation is a point mutation in the beta-globin gene (HBB) on chromosome 11, causing a Glu6Val substitution in the beta chain. This yields hemoglobin S (HbS), which polymerizes when deoxygenated and distorts red blood cells.

Inheritance is autosomal recessive. Homozygous HbSS results in sickle cell disease; heterozygous HbAS individuals are typically asymptomatic but may have mild sickling under low oxygen, and the allele provides some protection against malaria. The HbS allele is most common in sub-Saharan Africa, the Mediterranean, the Middle East, and parts of India.

Pathophysiology involves deoxygenated HbS polymerizing into fibers, distorting red cells, causing hemolysis and vaso-occlusion that leads to painful crises, ischemia, organ damage, and increased infection risk.

Clinical features of sickle cell disease include recurrent pain crises, chronic anemia, jaundice, splenic sequestration, acute chest syndrome, stroke, and progressive organ damage. Carriers are typically asymptomatic.

Diagnosis relies on newborn screening with hemoglobin electrophoresis or high-performance liquid chromatography; DNA testing can confirm HBB Glu6Val. The presence of HbF and other hemoglobin variants can modify severity.

Management focuses on prevention and symptom relief, including hydroxyurea to increase fetal hemoglobin, transfusions, vaccination, pain management, hydration, penicillin prophylaxis in children, and, in selected cases, hematopoietic stem cell transplantation or gene therapy.