A neonate with Hb Bart's hydrops fetalis has four defective alpha-globin genes. Which hemoglobin tetramers form Hb Bart's, and what is its oxygen affinity?

• A Beta-4 tetramers with very high O2 affinity, causing tissue hypoxia
• B Delta-4 tetramers with very low O2 affinity, causing haemolysis
• C Alpha-2/gamma-2 tetramers with normal O2 affinity but unstable structure
• D Gamma-4 tetramers with very high O2 affinity, causing tissue hypoxia ✓

Explanation

When all four alpha-globin genes are deleted (alpha-thalassemia major), gamma chains form gamma-4 tetramers called Hb Bart's. These tetramers have an extremely high oxygen affinity (leftward O2 dissociation curve) and fail to deliver oxygen to tissues, resulting in severe fetal hypoxia, heart failure, and hydrops fetalis, which is almost always fatal in utero or at birth. Beta-4 tetramers (HbH) form in three-gene deletion alpha-thalassemia and cause haemolytic anaemia but are less severe.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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