Potential new approaches to the management of the Hb Bart’s hydrops fetalis syndrome: the most severe form of a-thalassemia

摘要

The a-thalassemia trait, associated with deletions removing both a-globin genes from 1 chromosome (genotype z aa/z--), is common throughout Southeast Asia. Consequently, many pregnancies in couples of Southeast Asian origin carry a 1 in 4 risk of producing a fetus inheriting no functional a-globin genes (z--/z--), leading to hemoglobin (Hb) Bart’s hydrops fetalis syndrome (BHFS). Expression of the embryonic a-globin genes (z-globin) is normally limited to the early stages of primitive erythropoiesis, and so when the z-globin genes are silenced, at ~6 weeks of gestation, there should be no a-like globin chains to pair with the fetal g-globin chains of Hb, which consequently form nonfunctional tetramers (g 4 ) known as Hb Bart’s. When deletions leave the z-globin gene intact, a low level of z-globin gene expression continues in definitive erythroid cells, producing small amounts of Hb Portland (z 2 g 2 ), a functional form of Hb that allows the fetus to surviveuptothesecondorthirdtrimester.Untreated,allaffectedindividualsdieatthesestagesofdevelopment.Prevention is therefore of paramount importance. With improvements in early diagnosis, intrauterine transfusion, and advanced perinatalcare,therearenowasmallnumberofindividualswithBHFSwhohavesurvived,withvariableoutcomes.Adeeper understanding of the mechanism underlying the switch from z- to a-globin expression could enable persistence or reactivation of embryonic globin synthesis in definitive cells, thereby providing new therapeutic options for such patients.