Fetal hemoglobin in β hemoglobinopathies: Is enough too much?

Abstract

Cell-based therapies inducing about 40% fetal hemoglobin (HbF), or a HbF-like hemoglobin in most erythrocytes, can-at least in the shortterm-effect a cure or near-cure of β hemoglobinopathies, which are humankind's most common Mendelian diseases. [1][2][3] In sickle cell disease, a point mutation in the normal β-globin gene (HBB) directs the synthesis of sickle hemoglobin (HbS), which polymerizes on deoxygenation, damaging the red cell and triggering a complex pathophysiology. HbF exerts a powerful anti-polymerization effect because the chances of both the HbF tetramer (α 2 γ 2 ) and the hybrid tetramer α 2 γβ S entering the polymer phase are nearly nil. 4 Hundreds of different HBB mutations cause β thalassemia where insufficient β-globin synthesis allows free unpaired α globin to accumulate, leading to ineffective erythropoiesis and severe anemia. γ-Globin pairs with α globin forming HbF and preventing, at its earliest stage, the pathophysiology of the β thalassemia phenotype.

Interaction of Thalassemia and Hb Variants in Southeast Asia: Genotype-Phenotype Relationship

“…In contrast, hemoglobinopathy is characterized by a qualitative or structural defect of globin chain synthesis. Thalassemic hemoglobinopathy is the combination of quantitative and qualitative features of globin chain synthesis such as Hb Constant Spring (Hb CS, α + -thalassemia-like effect) and hemoglobin E (Hb E, β + -thalassemia) [12]. Hereditary persistence of fetal hemoglobin (HPFH) and δβ-thalassemia are characterized by elevated fetal hemoglobin (Hb F) levels in adult life.…”