Saturday, November 10, 2012

THALASSEMIAS


THE THALASSEMIAS

Thalassemia is derived from Greek word for sea, thalassa, because all the early cases of β thalassemia were described in children of Mediterranean origin. In thalassemia there is deficiency of globin chain synthesis. These are the commonest autosomal recessive disorders. The most common and clinically significant forms are α and β thalassaemia and the β thalassaemia like structural variant, HbE. Thalassemia is the quantitative defect in contrast to hemoglobinopathies which are qualitative defect, in globin chain synthesis. Thalassemia may be subdivided into,

α-Thalassemia - Complete or partial deficiency of synthesis of α-globin chain
β-Thalassemia - Complete or partial deficiency of synthesis of β-globin chain

In case of α thalassaemia since it has duplicate copy that can compensate the abnormality in another copy. Thus α thalassemia is clinically significant only when three or four α globin genes are lost. But in β thalassaemia there is only one copy so it is clinically significant.
The clinical manifestation of defect in all four α genes is seen during early fetal life since HbF requires α chain (α2γ2). By contrast manifestation of defect in β chain synthesis will be seen only after switch from fetal γ to adult β gene expression after birth. This switch is gradual, and clinical problems of abnormalities in β-globin synthesis rarely results before 3 month of age.

α-THALASSAEMIA

This is common in south-east Asia, where carrier rates may reach 50%, it is also widely distributed among Chinese, Asian, Indian population. In this condition there is decreased α globin chain synthesis (either heterozygous or homozygous). The majority of cases are due to deletion of one or both α globin genes. 

Hemoglobin Bart’s hydrops fetalis is the most severe form of α thalassemia where all four α genes are affected, abolishing all α chain synthesis. The disease is manifested during fetal life with the failure of normal production of fetal hemoglobin (α2γ2), there is surplus fetal γ chains that combines to form tetramers (γ4) recognized electrophoretically as Hb Bart’s. 

The fetus only survives in utero due to presence of embryonic Hb, Hb Portland (ζ2γ2). Hb Bart’s posses markedly increased oxygen affinity and thus cannot deliver oxygen. In an attempt to compensate for impaired tissue oxygen delivery, there is erythroblastosis with extramedullary haemopoiesis leading to hepatospleenomegaly. Increased capillary permeability due to tissue hypoxia compounded by cardiac failure due to anaemia lead to fetal hydrops and death in utero or stillbirth in late pregnancy.

HbH disease results when there is loss of function of three out of four α genes. There is sufficient residual α chain synthesis to allow production of normal fetal and adult hemoglobin, and fetal development is generally normal. After birth, the excess β chains produced form tetramers detectable electrophoretically as fastest variant HbH (β4). HbH precipitates within red cells with the formation of inclusion bodies leading to shortened red cell survival. Most patients have mild to moderate haemolytic anaemia, exacerbated during pregnancy or folate deficiency accompanied by splenomegaly. 

As in other congenital haemolytic anaemias, there is an increased tendency to form pigment gallstones. HbH tends to precipitates as inclusion body in the presence of redox dye brilliant cresyl blue and serves as useful diagnostic marker. Here HbA2 and HbF are within reference level. CBC shows moderately reduced Hb, markedly reduced MCV, MCH, and slightly raised red cell count. 

Phenotype
Number of functional α genes
Genotype
%Hb Bart’s at birth
HbH inclusions
Normal
4
αα/αα
0
None
α thalassaemia trait (minor)
3
-α/αα
0-2
None
2 (thalassemia major)
-α/-α (α+ thalassemia) or --/αα (α0 thalassemia)
Deletion may be cis or trans
2-8
Occasional
HbH disease
1
-/-α
10-40
Numerous
Hb Bart’s hydrops fetalis
0
--/--
80
Present in some cases

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