Etiology

• Cause: gene mutations

  • Beta thalassemia: usually due to point mutations in promoter sequences or splicing sites

    • β-globin locus - short arm of chromosome 11

  • Alpha thalassemia: usually due to deletion of at least one out of the four existing alleles

    • The α-globin gene cluster is located on chromosome 16

• Inheritance pattern: autosomal recessive

In a normal cell, the α-globin chains are coded by a total of four alleles. Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles.

• Silent carrier (minima form): one defective allele (-α/αα)

• Alpha thalassemia trait (minor form)

  • Two defective alleles (-α/-α or --/αα)

  • Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations

  • Children of parents with a two-gene deletion in cis are at higher risk of developing Hb Bart.

• Hemoglobin H disease (intermedia form): three defective alleles (--/-α) → results in excessive production of pathologically altered HbH

• Hemoglobin Bart's disease (major form): four defective alleles (--/-‑) → results in excessive production of pathologically altered Hb Bart (consists of four γ-chains (γ-tetramers))

In a normal cell, the β-globin chains are coded by a total of two alleles. Thus, there are two main forms of the disease.

• Beta-thalassemia minor (trait): one defective allele

• Beta-thalassemia major (Cooley anemia): two defective alleles

• Sickle cell beta thalassemia: a combination of one defective β-globin allele and one defective HbS allele

• Hemoglobin E/beta thalassemia: a combination of one allele with a hemoglobin E (HbE) variant and one defective β-globin allele. Produces a highly heterogeneous clinical spectrum, and in severe cases patients present with features of beta-thalassemia major. [3]

• Hemoglobin E disease: a condition characterized by homozygosity to the HbE variant. Patients can present with mild features resembling beta-thalassemia minor (i.e., mild anemia).

Anemia results from a combination of inefficient erythropoiesis and increased hemolysis. The degree to which both mechanisms contribute to the severity of the disease depends on a patient's exact genotype.

• Inefficient erythropoiesis → anemia

  • Beta-thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2.

    • HbF protects infants up to the age of 6 months, after which HbF production declines and symptoms of anemia appear.

  • Alpha-thalassemia intermedia (HbH disease) and alpha-thalassemia major (Bart's disease): faulty α-globin chain synthesis → ↓ α-chains → impaired pairing of α-chains with β-chains and γ-chains→ ↑ free β-, γ-chains → ↑ HbH, ↑ Hb-Bart's

  • In minor and minima forms, production of the affected chain is reduced, but enough is produced to prevent severe anemia.

• Increased hemolysis: One of the chains (either α or β) is reduced → compensatory overproduction of other chains → excess globin chains precipitate and form inclusions within RBCs → erythrocyte instability with hemolysis

• Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities