Hemoglobinopathies

The hemoglobinopathies are all genetic diseases of hemoglobin. They fall into two main groups: structural hemoglobin variants and syndromes with abnormal genetic production – thalassemias

Structural hemoglobin variants
Abnormal hemoglobin variants are caused by structural defects resulting from an altered amino acid sequence in the α or β chains. Clinicians distinguish among genetic variants such as HbS, HbC, or HbM.

HbS variant is manifested by disease called sickle cell disease. It is autosomal recessive inhereted hemolytic anemia with growth disorder, splenomegaly, and „crisis“. Crisis stands for an acute condition with red blood occlusion of capilaries involving limbs, spleen or lungs. This occlusion is triggered by stress conditions such as high altitude. Without medical treatment, this disorder is lethal.

The genetic defect of sickle cell anemia is substitution of one nucleotide (A>T) resulting into conversion of glutamic acid into valine in 6. position of 146 amino acids long β chain. This mutation produces rod-like aggregation of HbS molecules changing erytrocyte cell morphology into „sickle-like“.

Similar clinical findings provide HbC hemoglobin. HbC has lysine substitution of glutamic acid again on 6. position of β chain. Thus, this chain is less soluble and precipitate in erytrocytes. Methemoglobins (HbM) are forms of hemoglobin which have their affinity of oxygen altered. This mutation fixes Fe3+ variant of iron which can’t bind oxygen. However, reductases convert Fe3+ form into Fe2+ form and thus HbM carriers are only cyanotic.

There are more genetic variants in Hb structure. Such as 2 amino acid substitutions in HbC Harlem or deletion of 5 amino acids in Hb Gun Hill. On the other hand, Hb Constant Spring has 31 more amino acids in its peptide chain due to mutation in stop codon. Hb Lepore variant was produced by fusion of δ chain and β chain.

Syndromes with abnormal genetic production – thalassemias
Thalassemias are common hemoglobin disorders characterized by abnormal hemoglobin production. There are two main types, alfa thalassemia (defective α chains) and beta thalassemia (β chains). After reduction of production of either chain, there is a relative abundance of the other. This leads to production of abnormal hemoglobin tetramers composed of all 4 same chains (i.e. alfa chains). Consequently, these tetramers have lower capacity for oxygen and higher precipitation rate in erytrocytes. Higher precipitation of these molecules causes destruction of membranes producing hypochromic anemia.

In alfa thalassemia there is disrupted production of fetal and adult hemoglobin. In severe forms of alfa thalassemia, fetus suffer from oxygen insufficiency and it leads into hydrops state. Most common genetic factor which leads to alfa thalassemia is deletion. There are four alleles for alfa chain gene. Deletion of one allele is without clinical findings (αα/α-), deletion of two (αα/-- or α-/α-) causes thalassemia minor with mild anemia, deletion of three (α-/--) leads to sever anemia and deletion of four (--/--) is lethal.

As for beta thalassemia, defects in production of β chain also produce anemia, however, starting 3 months after birth when synthesis of HbF (γ chain) is physiologically subsituted by HbA (α chain). α chains precipitate in abundance in bone marrow causing ineffective erytropoesis. Heterozygotes (β/-) have mild anemia similar to one with iron deficiency (thalassemia minor). Cases with thalassemia major have severe anemia and bones changes due to bone marrow enlargement. Contrary to alfa thalassemia‘s, beta thalassemia mutations are based on nonsense, frameshift or splicing mutations.