An infant born to a Greek immigrant appears healthy at birth but develops transfusion-dependent hemolytic anemia by the age of 6 months. His erythrocytes contain insoluble aggregates of hemoglobin subunits. The child developed normally in utero because at that time he produced high quantities of:

Question

An infant born to a Greek immigrant appears healthy at birth but develops transfusion-dependent hemolytic anemia by the age of 6 months.  His erythrocytes contain insoluble aggregates of hemoglobin subunits.  The child developed normally in utero because at that time he produced high quantities of:

Quizplus · Accepted Answer

In adults, hemoglobin A is the predominant form of hemoglobin. It is a tetramer consisting of two alpha and two beta chains. Normally the synthesis of alpha and beta chains is tightly regulated such that one α-chain is synthesized for every β-chain. Hemoglobin formation begins within a few weeks of conception. The initial hemoglobin formed by a fetus in utero is called embryonic hemoglobin (Gower). This hemoglobin is composed of two zeta (ζ) and two epsilon (ε) chains (ζ2ε2) and is produced in the embryonic yolk sac. Within a few weeks the fetal liver starts synthesizing hemoglobin F (fetal hemoglobin). This form of hemoglobin is composed of two alpha and two gamma chains (α2γ2). HbF is the major hemoglobin in the fetus during last few months of gestation and in infants during first few weeks of postnatal life. HbA synthesis starts during the final month of gestation and gradually replaces HbF during postnatal life. Knowing the chronology of fetal hemoglobin formation and the gradual transition to adult hemoglobin (HbA) is important in understanding the relationship between clinical manifestations and postnatal age in beta thalassemia. Thalassemias are hereditary hemolytic anemias resulting from defective synthesis of globin chains. As described above, the synthesis of alpha and beta globin chains is very coordinated. In patients with thalassemia, the synthesis of either alpha or beta chains is defective. Beta thalassemia is caused by defective synthesis of beta chains. There are two copies of the beta globin gene (one from each parent). If only one gene is defective the patient will have beta thalassemia trait (beta thalassemia minor) and lack significant anemia. A defect in both beta globin genes results in severe hemolytic anemia known as beta thalassemia major. In this disease, alpha chains are produced normally but they cannot form stable tetramers due to the lack of beta globin chains. This failure to form stable hemoglobin leads to precipitation of alpha globin chains and premature lysis of red blood cells. Beta thalassemia cannot become symptomatic as long as there are significant amounts of gamma chains present because gamma chains make up for the absence of HbA beta chains in forming tetramers. Thus, in late gestation and early postnatal life, the expression of hemoglobin A is offset by gamma chain production (Choice C). As gamma chain production wanes, patients will become symptomatic. (Choice A) α-globin is a normal component of both HbA and HbF. α-globin synthesis is defective in α-thalassemia but it is normal in β-thalassemia. α-globin is able to combine with γ-globin to form HbF. This allows patients with β-thalassemia major to be asymptomatic in utero and in the first few months following birth. (Choice B) β-globin synthesis is defective in patients with b-thalassemia. (Choice D) δ-globin is a minor globin gene that is expressed at very low levels in normal adults. Two α-globins and two δ-globins combine to form hemoglobin A2. (Choice E) ζ-globin is a component of hemoglobin Gower, the initial hemoglobin formed by the embryo very early in embryogenesis. Educational Objective: HbF contains γ-globin instead of β-globin. Patients with homozygotic β-thalassemia (β-thalassemia major) are asymptomatic at birth due to the presence of γ-globins and HbF. Switching to HbA production and the cessation of γ-globin synthesis precipitates the symptoms of β-thalassemia.

An Infant Born to a Greek Immigrant Appears Healthy at Birth