Thalassemia: Genetics, Distribution, and Classification

• Thalassemia is a heterogenous group of disorders characterized by a genetically determined reduction in the rate of normal globin chain synthesis.

Geographical Distribution

• Thalassemia is found in parts of the world where malaria is common.
• It occurs most frequently in people from Mediterranean countries, North Africa, the Middle East, India, and Central & Southeast Asia.

Genetics

• Hemoglobin A consists of 2 alpha and 2 beta chains.
• Alpha chain synthesis is controlled by 2 gene clusters on chromosome 16.
• Beta chain synthesis is controlled by a gene on chromosome 11.

Classification

• Thalassemia are autosomal recessive disorders.
• Thalassemia is classified according to the deficient globin chain.

Alpha Thalassemia

• Alpha chains of globin are not or partly synthesized.
• Alpha chains are required for both HbA and HbF.
• The majority of alpha thalassemia cases result from gene deletions.
• Others result from mutations which cause aberrant splicing and chain terminator codon, or mutations that instigate alpha globin instability

Classification of Alpha Thalassemia

• Normal genotype: αα/αα
• Silent carrier genotype: αα/-α
• Thalassemia trait/minor genotype: αα/--
• HbH disease genotype: --/-α
• Hb Barts/Hydrops foetalis syndrome genotype: --/--

Number of Genes Present in Alpha Thalassemia

• Silent carrier has 3 genes present.
• Alpha thalassemia trait has 2 genes present.
• Hemoglobin H disease has 1 gene present.
• Hb Barts / Hydrops fetalis has 0 genes present.

Inheritance of Thalassemia

• Children can inherit thalassemia traits or hemoglobin H disease depending on the parents' genotypes.

Pathophysiology in Alpha Thalassemia

• There is reduced biosynthesis of the alpha chain.
• Beta and gamma chains are produced.
• In fetuses, a Y tetramer is present when alpha is absent which is unable to carry and deliver oxygen causing Intra uterine hypoxia and potentially foetal death and/or still birth.
• In adults, a formation of beta tetramer is present in developing normoblast.
• Ineffective erythropoiesis is moderately observed.
• Hb H inclusion in red cells cannot dissociate oxygen in tissue.
• Consequently Spleen traps these cells, which leads to Tissue hypoxia and Hemolytic anemia.

HB BARTS' Hydrops Foetalis Syndrome

• Deletion of all 4 genes.
• Intrauterine death occurs, or if born, the baby dies within the first 2 hours.
• Hb barts' (γ4) cause a high affinity for oxygen; and therefore impairs oxygen dissociation causing severe tissue hypoxia concluding in foetal and or foetal death.

Hb H

• Genotype --/-alpha
• Anemia is present with Hb levels of 7-11g/dl.
• Reticulocyte count ranges from 4-15%.
• Icterus and hepatosplenomegaly are evident.

Lab Findings in Hb H

• Anisopoikilocytosis and Hypochromia
• Microcytosis and Target cells are prevalent.
• Hb electrophoresis demonstrates a fast moving HbH band in the range of 5-35%.
• Hb H can also demonstrate presence on HPLC.

Alpha -Thaassemia Trait

• Deletion of two (-α/-α) (--/ αα)
• Patients are clinically normal
• Haemoglobin 9-12 g/dl
• MCV and MCH are low
• Mild microcytosis and hypochromia is detected.
• Hb electrophoresis Hb bart is : not demonstrable
• These individuals are often mistakenly diagnosed as having iron deficiency anaemia, but RDW is a useful marker.

Silent Carrier

• The deletion of one globin gene is present (- α/αα).
• People with this condition are usually haematologically and clinically normal
• Confirmation is achieved by DNA analysis.