From a pathophysiological point of view, the clinical consequences of β-thalassemia are due to an excess of α-chains, which are unable to associate and are highly unstable. In nor mal erythropoiesis, α-globins are associated with β-globins via AHSP (α-chain stabilization protein). Free α chains behave as active oxidants capable of causing apoptosis and thus inducing ineffective erythropoiesis. The main difference between α and β-thalassemias is that α-thalassemias are hemolytic diseases, while β-thalassemias are dyserythropoietic diseases. Furthermore, β-thalassemias are predominantly due to point mutations or short insertions/deletions of a few nucleotides, not extensive deletions like the α-thalassemic forms. From a translational point of view, the β-thalassemias are distinguished in β+ forms and β0 forms. In β+-thalassemias, mutated alleles encode for reduced amounts of mRNA and thus β-globin, with wide variations depending on the type of mutation and with normal or abnormal chain (e.g., HbE, Hb Knossos). In β0-thalassemias, the mutation completely prevents the production of mRNA, and therefore there is an absence of β globin.

The main molecular mechanisms underlying β-thalassemias involve mutations affecting:

• Promoters, so the transcription efficiency is decreased (the consequence is a β+-thalassemia).

 • Splicing, which is completely abolished due to abnormalities of the exon–intron junction leading to β0-thalassemia.

 • Splicing, in which the incorrect position of the splicing itself results in structural anomalies leading to β+-thalassemia; the typical example of this anomaly is HbE.

 • Splicing, in which an alternative splicing sequence results in a premature stop codon leading to β+-thalassemia with expressed protein rapidly eliminated by proteolysis; the typical example of this anomaly is Hb Knossos.

• Introns (e.g., intron-1 at 110 G → A), with the creation of a new splicing acceptor site leading to β+-thalassemia. Another mutation creates a GT donor site that, interacting with the normal acceptor, unmasks a new acceptor that interacts with the normal donor, leading to the division of intron-2 into two separate introns with a reduction of chain production; also, in this case, β+-thalassemia is observed.

 • Polyadenylation site, where there is inefficient cutting and defective polyadenylation at the normal site, resulting in long and unstable mRNA and reduced production of normal mRNA leading to β+-thalassemia is observed.

• Translation, in which the cause is the formation of a non-sense codon; for example, at codon 36, the CAG → TAG mutation is typically present in Sardinia and is frequent in the Mediterranean; at codon 17, the AAG → TAG mutation is frequent in Asians and Chinese (such mutations do not allow the expression of globin, and therefore we are dealing with β0-thalassemias).

 • Exons in which microdeletions or small insertions cause a frameshift and premature stop signal, with the expression of highly unstable globin that is oxidizing and toxic for the erythroid cell (the condition causes severe hemolytic anemia also in the heterozygote and is known as dominant thalassemia).

Among the about 200 defects causing β-thalassemia, 20 are due to deletion. These variants are quite rare, except for the 619 bp one that is frequently found in south-eastern Asia. Among them, there are also two forms present with a certain frequency in the Mediterranean area:

• Hereditary persistence of fetal hemoglobin (HPFH), a deletion syndrome characterized by decreased/absent production of β-globin and variable compensatory increase of γ-globin, is present in Mediterranean and African subjects, sometimes with double HPFH/HbS het erozygosity. Some HPFH deletions are very large and can reach up to 100 kb. There are also HPFH forms due to nondeletion that are classified as forms with only increased globin Aγ and forms with only increased globin Gγ.

• δβ-thalassemia: in the heterozygote state, it is very similar to the β-thalassemia, with the difference of increased levels of HbF included between 5% and 15% and a characteristic cellular distribution (F cells); the homozygotes and the double heterozygotes δβ/β-thalassaemia have a picture similar to thalassemia intermedia or major. The δβ-thalassemia is subdivided into two groups, within which there are further differences in the deletions:

– δβ-thalassemias with the production of Aγ and Gγ chains, called AγGγ (δβ)0-thalassaemias; in them are included the Hb Lepore, hemoglobins whose globin chains are the result of unequal crossing-over δβ.

– δβ-thalassemias with the production of Gγ only, called Gγ (Aγδβ)⁰-thalassemias.

HPFH and δβ-thalassemia are strictly related from a molecular point of view, and the distinction has mainly clinical value; however, some forms of HPFH are due to puncti form mutations, which denotes their heterogeneity with respect to δβ-thalassemia. The heterozygote for HPFH has a normal hematological picture with normal indices, normal HbA2, and HbF between 15% and 30% with homogeneous pan-cellular distribution. The homozygote for HPFH is hematologically normal, except for a reduction of the MCV and MCH indexes, and so also appears the double heterozygote HPFH/β-thalassaemia.

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مواضيع ذات صلة

liquid biopsy (Fluid biopsy, Fluid phase biopsy)

lipoproteins (High-density lipoproteins [HDLs, HDL-C], Low density lipoproteins [LDLs, LDL-C], Very-low-density lipoproteins [VLDLs], Lipoprotein electrophoresis, Lipoprotein phenotyping, Lipid fractionation, Non-HDL cholesterol, Lipid profile)

lipoprotein-associated phospholipase A2 (Lp-PLA2 PLAC test)

Hemolytic Anemias

Sickle Cell Anemia (Hemoglobinopathy S, Sickle Cell Disease)

Laboratory Diagnosis (Phenotypic) of Thalassemias

lipase (Pancreatic lipase, Lipoprotein lipase)

leucine aminopeptidase (LAP)

Legionnaires disease antibody test

Sideropenic and Assimilated Anemia

Automated Differential Count

Differential Leukocyte Count (Leukocyte Formula)