Phenotypegenotype relationships

The P-thalassaemias show remarkable phenotypic variability, ranging from severe life-threatening anaemia to an extremely mild condition that may be identified only by chance. The molecular basis for this diversity is at least partly understood (Figure 6.5).

The genetic modifiers of the P-thalassaemia phenotype can be divided into primary, secondary and tertiary. Primary modifiers are the different mutations which, because of their variable effects on P-globin gene expression, may affect the output of P-globin chains, ranging from zero to a very mild reduction. Secondary modifiers are those that reduce the degree of imbal-

Figure 6.4 The pathophysiology of P-thalassaemia.

a2Y2 A' HbF

Selective survival of HbF-containing precursors


Denaturation Degradation m


Increased levels of HbF in red cells

Splenomegaly (pooling, plasma volume expansion)

High oxygen affinity of red cells


Reduced \ / Tissue

O2 delivery \ ^ hypoxia


Marrow expansion

Skeletal deformity Increased metabolic rate Wasting Gout Folate deficiency

Increased iron absorption

Destruction of RBC precursors

Ineffective erythropoiesis


Reduced \ / Tissue

O2 delivery \ ^ hypoxia



Iron loading

Endocrine deficiencies Cirrhosis Cardiac failure a

ance of globin chain synthesis. They include the co-inheritance of a-thalassaemia and a variety of ill-understood genetic modifiers of y-chain production in adult life. Although several genes with the latter property have been identified, it seems likely that many remain to be discovered. Tertiary modifiers are those that affect the complications of disease; the severity of bone disease, iron loading and jaundice may be affected by polymorphisms of genes involved in the metabolic pathways concerned with these complications. Similarly, it seems very likely that the propensity to infection is modified by polymorphisms involving the immune system and its regulation. Finally, it should be remembered that environmental factors, long neglected, may also play an important role in modifying the P-thalassaemic phenotype.

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