Sickle Cell Anemia: Genetic Basis and Pathophysiology

Sickle cell disease (SCD) is an **autosomal recessive** disorder caused by a **point mutation (Glu6Val) in the β-globin gene (HBB)** on chromosome 11.

Molecular Consequence

• Mutant hemoglobin S (HbS) polymerizes under deoxygenation → rigid, sickle-shaped RBCs.
• Hemolysis (anemia, jaundice, gallstones), vaso-occlusion (pain crises, organ infarction), endothelial activation, chronic inflammation.

Genotypes

• HbSS (sickle cell anemia) – most severe.
• HbSC, HbS/β-thalassemia – variable severity.
• HbAS (sickle cell trait) – generally asymptomatic; malaria protection.

Complications

Acute chest syndrome, stroke, splenic sequestration, priapism, avascular necrosis, nephropathy, retinopathy, infections (functional asplenia).

Disease-Modifying Therapies

• Hydroxyurea (induces HbF).
• Voxelotor (inhibits HbS polymerization).
• Crizanlizumab (anti-P-selectin).
• L-glutamine.
• Curative: Allogeneic HSCT (matched sibling), gene therapy (lentiviral β-globin addition, CRISPR editing).