Thalassemia
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Thalassemia (American English) (or Thalassaemia in British English) is an inherited disease of the red blood cells, classified as a hemoglobinopathy. The genetic defect results in synthesis of an abnormal hemoglobin molecule. The blood cells are vulnerable to mechanical injury and die easily. To survive, many people with thalassaemia need blood transfusions at regular intervals.
Being a carrier of the disease confers a degree of protection against malaria, and is quite common among people from Italian or Greek origin, since malaria was widespread in those countries at a time. In that respect it resembles another genetic disease, sickle-cell anemia.
The thalassemias are classified according to which chain of the globin molecule is affected: in α thalassemia, the production of α globin is deficient, while in β thalassemia the production of β globin is defective. Thalassemia produces a deficiency of α or β globin, unlike sickle-cell anemia which produces a specific mutant form of β globin.
Both α and β thalassemia are inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. If both parents carry a hemoglobinopathy trait, there is a 25% chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families that carry a thalassemia trait.
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Autosomal recessive inheritance
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Alpha thalassemias
The alpha thalassemias involve the genes HBA1 (Template:OMIM) and HBA2 (Template:OMIM). α thalassemias result in excess β chain production in adults and excess γ chains in newborns. The excess β chains form unstable tetramers that have abnormal oxygen dissociation curves.
There are four genetic loci for α globin. The more of these loci that are deleted or affected by mutation, the more severe will be the manifestations of the disease.
If all four loci are affected, the fetus cannot live once outside the uterus: most such infants are dead at birth with hydrops fetalis, and those who are born alive die shortly after birth. They are edematous and have little circulating hemoglobin, and the hemoglobin that is present is all tetrameric γ chains (hemoglobin Barts).
If three loci are affected, Hemoglobin H disease results. Two unstable hemoglobins are present in the blood, both hemoglobin Barts and hemoglobin H (tetrameric β chains). There is a microcytic hypochromic anemia with target cells and Heinz bodies on the peripheral blood smear. The disease may first be noticed in childhood or in early adult life, when the anemia and splenomegaly are noted.
If two of the four α loci are affected, α-thalassemia trait results. Two α loci permit nearly normal erythropoiesis, though there is a mild microcytic hypochromic anemia. There is a high prevalence (about 30%) of deletion of one of the two α loci on chromosomes of people of recent African origin, and so the inheritance of two such chromosomes is not uncommon. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron.
If one of the four α loci is affected, there is minimal effect. Three α-globin loci are enough to permit normal hemoglobin production, and there is no anemia or hypochromia in these people. They have been called α thalassemia carriers.
Beta thalassemias
Beta thalassemia is due to mutations in the HBB gene HBB (Template:OMIM). In β thalassemia, excess α chains are produced, but these do not form tetramers: rather, they bind to the red blood cell membranes, producing membrane damage. The severity of the damage depends on the nature of the mutation. Some mutations (βo) prevent any formation of β chains; others (β+) allow some β chain formation to occur.
There are two β globin genes. If both have thalassemia mutations, a severe anemia called β thalassemia major or Cooley's anemia results. Untreated, this results in death before age twenty: treatment consists of periodic blood transfusion; splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload. Cure is possible by bone marrow transplantation.
If only one β globin gene bears a mutation, β thalassemia minor results. This is a mild anemia with microcytosis. Symptoms include weakness and fatigue - in most cases β thalassemia minor may be asymptomatic and many people may be unaware they have this disorder. Detection usually involves counting the mean corpuscular volume (size of red blood cells) and noticing a slightly decreased mean volume then is normal.
The actual genetic cause of β thalassemias are actually very diverse and a number of different mutations can cause reduced or absent β globin synthesis. Mainly there are two forms of genetic defects which produce β thalaseemias.
Nondeletion forms:
These defects generally involve a single base substitution or small deletion or inserts near or upstream of the β globin gene.
Deletion forms:
Deletions of different sizes involving the β globin gene produce different syndromes such as (βo) or hereditary presistance of fetal hemoglobin syndromes.
In combination with other hemoglobinopathies
Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:
- hemoglobin E/thalassemia: common in Cambodia and Thailand, clinically similar to β thalassemia major
- hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically similar to sickle cell anemia, with the additional feature of splenomegaly
- hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β+ thalassemia produces a milder disease.
Complications of tranfusions
Repeated transfusions leads to the accumulation of iron in the heart and liver. If untreated it invariably leads to death (by heart failure). Complications with high iron levels can be avoided through the use of chelators such as deferoxamine (also called desferrioxamine) and deferiprone. Of the two, deferoxamine is preferred; it is associated with fewer side-effects.[1]
Thalassemia in Cyprus
A screening policy exists on both sides of the island of Cyprus to reduce the incidence of thalassemia, which since the program's implementation in the 1970s (which also includes pre-natal screening and abortion) has reduced the number of children born with the hereditary blood disease from 1 out of every 158 births to almost zero.
References
1. Maggio A, D'Amico G, et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells Mol Dis. 2002 Mar-Apr;28(2):196-208. PMID 12064916.
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