A mainstay of therapy is hydroxyurea, a “gentle” inhibitor of DNA synthesis. Hydroxyurea reduces pain crises and lessens the anemia through several effects, including (1) an increase in levels of HbF; (2) an anti-inflammatory effect because of the inhibition of white cell production; (3) an increase in red cell size, which lowers the intracellular hemoglobin concentration; and (4) its metabolism to NO, a potent vasodilator and inhibitor of platelet aggregation. Encouraging results also have been obtained with allogeneic bone marrow transplantation, which is potentially curative.
Thalassemias are inherited disorders caused by mutations in globin genes that decrease the synthesis of α-or β-globin. Decreased synthesis of one globin results not only in a deficiency of Hb, but also in red cell damage that is caused by precipitates formed from excess unpaired “normal” globin chains. The mutations that cause thalassemia are particularly common in Mediterranean, African, and Asian regions in which malaria is endemic. As with HbS, it is hypothesized that globin mutations associated with thalassemia protect against falciparum malaria.
A diverse collection of α-globin and β-globin mutations underlies the thalassemias, which are autosomal codominant conditions. As described previously, adult hemoglobin, or HbA, is a tetramer composed of two α chains and two β chains. The α chains are encoded by two α-globin http://ebooksmedicine.net
Table 12.3 Clinical and Genetic Classification of Thalassemias genes lying in tandem on chromosome 16, whereas the β chains are encoded by a single β-globin gene located on chromosome 11. The clinical features vary widely depending on the specific combination of mutated alleles that are inherited by the patient (
Table 12.3), as described next.
Mutations associated with β-thalassemia fall into two categories: (1) β0, in which no β-globin chains are produced; and (2) β+ , in which there is reduced (but detectable) β-globin synthesis. Sequencing of β-thalassemia genes has shown more than 100 different causative mutations, a majority consisting of single-base changes. Persons inheriting one abnormal allele have β-thalassemia minor (also known as β-thalassemia trait), which is asymptomatic or mildly symptomatic. Most people inheriting any two β0 and β+ alleles have β-thalassemia major; occasionally, persons inheriting at least one β+ allele have a milder disease termed β-thalassemia intermedia. In contrast with α-thalassemia (described later), gene deletions rarely underlie β-thalassemia (
Table 12.3
The mutations responsible for β-thalassemia are diverse and disrupt β-globin synthesis in several different ways. The most common mutations lead to abnormal RNA splicing, whereas others fall in the β-globin gene promoter or coding regions. The specific nature of the mutation determines whether the outcome is a β+ or β0 allele.
Defective synthesis of β-globin in β-thalassemia contributes to anemia through two mechanisms: (1) inadequate HbA formation, resulting in small (microcytic), poorly hemoglobinized (hypochromic) red cells; and (2) by allowing the accumulation of unpaired α-globin chains, which form toxic precipitates that severely damage the membranes of red cells and erythroid precursors. A high fraction of erythroid precursors are so badly damaged that they die by apoptosis (