Thalassemia syndromes are a heterogenous group of inherited disorders caused by genetic lesions leading to decreased synthesis of either alpha or beta globin chain of Hb A.
The β-globin 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
Individuals inheriting one abnormal allele have thalassemia minor or thalassemia trait, which is asymptomatic or mildly symptomatic.
Most individuals inheriting any two β0 and β+ alleles have β-thalassemia major;
occasionally, individuals inheriting two β+ alleles have a milder disease termed β-thalassemia intermedia
The reduced synthesis of β-globin leads to inadequate HbA formation, so that the MCHC is low, and the cells appear hypochromic and microcytic.
more important is red cell hemolysis, which results from the unbalanced rates of β-globin and α-globin chain synthesis.
Unpaired α chains form insoluble aggregates that precipitate within the red cells and cause membrane damage that is severe enough to provoke extravascular hemolysis
intramedullary destruction of erythroid precursors (ineffective erythropoiesis) causes inappropriate increase in the absorption of dietary iron, which often leads to iron overload.
Most of the α-thalassemias are caused by deletions that remove one or more of the α-globin gene loci. The severity of the disease that results from these lesions is directly proportional to the number of α-globin genes that are missing
For example, the loss of a single α-globin gene is associated with a silent-carrier state, whereas
the deletion of all four α-globin genes is associated with fetal death in utero, because the blood has virtually no oxygen-delivering capacity.
With loss of three α-globin genes there is a relative excess of β-globin or chains other than α-globin. Excess β-globin forms relatively stable β4 tetramers known as HbH that cause less membrane damage than do free α-globin chains.
In all gene deletions, gamma4 tetramer is present known as Hb Bart.
The hemolytic anemia and ineffective erythropoiesis tend be less severe in α-thalassemia than in β-thalassemia.
Unfortunately, both HbH and Hb Bart have an abnormally high affinity for oxygen, which renders them ineffective at delivering oxygen to the tissues.
Clinical features :
mainly for thalassemia majors:
(microcytic), pale (hypochromic), Target cells , poikilocytosis, anisocytosis, and reticulocytosis. Nucleated red cells (normoblasts)
hyperplasia of erythroid progenitors, with a shift toward early forms.
The expanded erythropoietic marrow may completely fill the intramedullary space of the
skeleton, invade the bony cortex, impair bone growth, and produce skeletal deformities – skull X-ray film shows crew cut appearence
splenomegaly, hepatomegaly, and lymphadenopathy
produce growth retardation and a degree of cachexia
Affected children fail to develop normally, and their growth is retarded from shortly after birth. They are sustained only by repeated blood transfusions, but gradually systemic iron overload develops
Unless steps are taken to prevent iron overload, over the span of years severe hemosiderosis develops, Unless patients are treated aggressively with iron chelators, cardiac failure
When feasible, bone marrow transplantation at an early age is the treatment of choice.