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Alpha Thalassemia

From SNPedia

Alpha-thalassemia (α-thalassemia, α-thalassaemia) is a form of thalassemia involving the HBA1 and HBA2 genes. Alpha-thalassemia is due to impaired production of alpha chains from 1, 2, 3 or all 4 of the alpha globin genes in a diploid cell, leading to a relative excess of beta globin chains. The degree of impairment is based on which clinical phenotype is present (how many genes are affected).Wikipedia

Types [1]
There are two carrier types (i.e., alpha+-thalassemia, also known as alpha thalassemia silent, and, alpha°-thalassemia, also known as alpha thalassemia trait), and there are two clinically relevant disorders (i.e., HbH disease and Hb Bart syndrome).

Note that affected (impaired) alleles are most often based on deletions (which in general are not assayed by the microarrays used by DTC genomics companies and so can not be reported via Promethease), although there are some deleterious single nucleotide variants known (which include ones reported in SNPedia and therefore Promethease). A list of known alpha-thalassemia variants is on the HBA2 page.

# Alleles affected Description Genotype
One This is known as alpha thalassemia silent since there is minimal effect on hemoglobin synthesis. Three normal α-globin genes are enough to permit normal hemoglobin production, and there are no clinical symptoms. The impaired allele may be based on either a single nucleotide variant (SNP) or on a deletion. -/α α/α
Two This genotype is known as alpha thalassemia trait, with two normal α genes permitting nearly normal production of red blood cells, but there may be a mild anemia. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron.

Alpha thalassemia trait can exist in two forms:

  • alpha-thal-1 (αα/--), involves cis deletion of both alpha genes on the same chromosome;
  • alpha-thal-2 (α-/α-), involves trans deletion of alpha genes this occurs on different (homologous) chromosomes.
-/- α/α or
-/α -/α
Three This condition is called Hemoglobin H disease (or HbH), representing two unstable hemoglobins present in the blood; Hemoglobin Barts (tetrameric γ chains) and Hemoglobin H (tetrameric β chains). Both of these unstable hemoglobins have a higher affinity for oxygen than normal hemoglobin. There is a microcytic hypochromic anemia as well as hepatosplenomegaly. The disease is noticed in childhood or in early adult life when anemia and hepatosplenomegaly are noted.

HbH is therefore caused by the complete deletion of the HBA1 and HBA2 genes on one chromosome 16, combined with a defect (deletional or nondeletional) in either the HBA1 or HBA2 gene on the other chromosome 16, leaving one functioning gene present.

-/- -/α
Four This is known as alpha thalassemia major as well as Hb Bart syndrome. Fetuses are edematous and have little circulating hemoglobin, and the hemoglobin that is present is all tetrameric γ chains. When all four alleles are affected, the fetus likely will not survive gestation without in utero intervention; most infants with alpha thalassemia major are stillborn with 'hydrops fetalis'. Fetuses treated with intrauterine transfusions throughout pregnancy starting at an early gestational age can survive to birth with acceptable morbidity. After birth, the treatment options include bone marrow transplantation or continued chronic transfusions.

Hb Bart is therefore caused by defects (deletional or otherwise) in both HBA1 and HBA2 genes on both chromosome 16's, resulting in no functional gene being present.

-/- -/-

Counseling [PMID 20507641OA-icon.png]

The implications for parents carrying alpha thalassemia variants are the following:

  • When both parents carry an αo thalassaemia mutation (--/αα) the risk of their offspring having Hb Bart's hydrops foetalis is 1:4 (25%).
  • When one parent carries αo thalassaemia (--/αα) and the other carries an α+ thalassaemia (-α/αα) the risk of their offspring having HbH disease is 1:4 (25%).
  • If the carrier of α+ thalassaemia is a homozygote clearly the risk of HbH disease is 1:2 (50%).

Note that since there are many different alleles of αo and α+ thalassaemia, genetic counselling may be more complex than outlined in this simple model.