Diagnostics

α-thalassemia (alpha-thalassemia)

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Overview
Diagnosis
Therapy

Alpha-thalassemia is caused by disruption of alpha-globin genes resulting in hypochrome, microcytic anemia of varying degree.

alpha-thalassemia: Overview

Alpha-(α-) thalassemia results from the disruption of one or more alpha-globin genes and are thus a quantitative disorder of the synthesis of alpha-globin chains. Alpha-thalassemia is particularly common in Asia, Arabia and Africa, and the Mediterranean countries.

The alpha-globin genes are organized on chromosome 16 in the alpha-globin cluster with other relatives of the alpha-globin genes. Human cells usually have a total of four alpha-globing genes, one HBA1 and one HBA2 gene on each of the two chromosomes 16: aa/aa.

The clinical picture of alpha-thalassemia ranges from asymptomatic carriers (α-thalassemia minima), to hypochromic, microcytic anemias of varying degree (α-thalassemia minor and HbH disease), to lethal hemolytic anemia called Hb Bart's hydrops fetalis syndrome. The total number of disrupted alpha-globin genes on both chromosomes is the main factor determining the clinical picture:

Genotype	Genetic classification	Clinical diagnosis	Symptoms	Hb	MCH	Hb separation
aa/aa	Wild-type	Normal findings	No pathology	Normal	Normal	Normal
-a/aa	Heterozygous a⁺-thalassemia	α-thalassemia minima	No to minor changes in CBC (microcytosis and hypochromia)	Normal	26 - 28 pg	Normal
-a/-a	Homozygous a⁺-thalassemia	α-thalassemia minor	Slight CBC changes (microcytosis and hypochromia), rarely mild anemia	Normal oder minimal erniedrigt	22 - 26 pg	Normal
--/aa	Heterozygous a⁰-thalassemia	α-thalassaemia minor	Slight CBC changes (microcytosis and hypochromia), mild anemia	Normal oder leicht erniedrigt	<24 pg	Normal, possibly slightly reduced HbA2
--/-a	Compound heterozygous a⁰/a⁺-thalassemia	HbH-disease (α-thalassemia intermedia)	Varying degree of microcytic hypochromic anemia.	8 - 10 g/dl	<22 pg	Detection of HbH (tetramer of 4 β-globin chains): HbH (β₄) up to about 20%
--/--	Homozygous a⁰-thalassemia	Hb Barts hydrops fetalis - syndrom (α-thalassemia major)	Pronounced intrauterine anemia; infants usually die intrauterine or shortly after birth	Intrauterine <6 g/dl	<20 pg	Hb Barts (γ₄): about 80 - 90%; occassionally HbH; Hb Portland (ζ₂γ₂, ζ₂β₂): about 10 - 20%

Due to inaequal crossing-over during meiosis, duplications of alpha-globing genes on one chromosome 16 may also occur. Most common is the triplication (aaa) of the alpha-globin gene on one chromosome 16, so that the patient has a total of five alpha-globin genes (aaa/aa); more rarely, higher-grade copy number gains also occur. Clinically, multiple copies of the alpha-globin gene are usually inconspicuous. However, when inherited concomitantly with beta-thalassemia, alpha-globin gene triplication leads to a greater imbalance between alpha- and beta-globin chains and thus to a more pronounced clinical picture of beta-thalassemia.

alpha-thalassemia: Diagnosis

Diagnosis or exclusion of alpha-thalassemia is made by a combination of blood count, iron status, hemoglobin separation, and molecular genetic testing.

Alpha-thalassemia is typically associated with hypochromic, microcytic anemia. The severity of blood count changes depends on the number of disrupted alpha-globin genes. Hemoglobin concentration ranges from normal values in alpha-thalassemia minima to severe anemia (Hb <6g/dl) in homozygous a⁰-thalassemia. The number of erythrocytes and their indices MCH and MCV behave accordingly. It should be noted that the values of the blood count may lie within the reference range in thalassemia minima which in those cases can only be detected by molecular genetic methods.

In carriers of sickle cell disease, changes in erythrocyte indices of a concomitant alpha-thalassemia are attenuated.

Patients with a triplication of alpha-globin genes do not show any blood count changes.

Iron status in alpha-thalassemia is usually normal. In pronounced forms with hemolysis, ineffective erythropoiesis and consequent need for repeated transfusions, iron overload with elevation of ferritin may occur.

Hemoglobin electrophoresis usually shows no abnormalities in α-thalassemia minima and minor (-a/aa, -a/-a, or --/aa), possibly with the fraction of HbA2 in the lower reference range or slightly below. In pronounced forms (--/-a), a tetramer of four beta-globin chains (β4) is detectable due to the lack of alpha-globin chains; this is referred to as hemoglobin HbH and accounts for approximately 20% of total hemoglobin. In thalassemia major, without production of alpha-globin chains, Hb Barts, a tetramer of four γ-globin chains (γ4), and occasionally in small amounts HbH and the embryonic hemoglobins Hb Portland-1 (ζ2γ2) and Hb Portland-2 (ζ2,β2) are formed.

Molecular genetic studies are necessary for unequivocal detection and definitive determination of the form of alpha-thalassemia. The most common cause of alpha-thalassemia is the loss of one or more alpha-globin genes due to deletions in the alpha-globin complex. These can be detected by multiplex ligation-dependent probe amplification (MLPA). The most common deletions include -a^3.7, -a^4.2, --^SEA, --^MED, --^FIL, --^THAI, -(a)^20.5. The -a^3.7 and -a^4.2 deletions cause the loss of one alpha globin gene and are referred to as a⁺-thalassemia. Due to their size, both alpha globins are disrupted in the other types of deletion. These are referred to as a⁰-thalassemias.

The most common cause of a+ thalassemia not caused by a deletion and detected by sequencing is Hb Constant Spring (aa^CS/aa). In this form, the stop codon of the HBA2 gene is affected, so that an extended alpha-globin chain is produced by this alpha-globin gene. However, this altered alpha-globin chain is unstable and leads to the clinical thalassemic picture.

alpha-thalassemia: Therapy

Therapy of alpha-thalassemia depends on the clinical classification and the presenting symptoms.

Current national recommendations and guidelines for treatment can be found at:

AWMF: https://www.awmf.org/leitlinien/detail/ll/025-017.html

Bain BJ. Haemoglobinopathy Diagnosis. Wiley-Blackwell 2020;3. Edition.

Busse B et al. Stufendiagnostik der Hämoglobinopathien. LaboratoriumsMedizin 2015;39(5):335-341.

Farashi S, Harteveld CL. Molecular basis of alpha-thalassemia. Blood Cells Mol Dis 2018;70:43-53.

Gesellschaft für Pädiatrische Onkologie und Hämatologie. S1-Leitlinie Thalassemian. Aktualisierung 01/2023. Verfügbar unter: https://www.awmf.org/leitlinien/detail/ll/025-017.html.

Kohne E. Hemoglobinopathies. Deutsches Ärzteblatt international 2011;108(31-32):532-540.

Thomas L 2022 Labor und Diagnose. www.labor-und-diagnose-2020.de. Ausgabe 30.06.2022.

Status: April 2024

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