Thalassemia

Thalassaemia is an inherited disease of the erythrocytes (the red blood
cells), classified as a hemoglobinopathy: the genetic disorder 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.

This disease tends to occur in areas with a past history of malaria, since
it confers a degree of protection against that disease. In that respect it
resembles another genetic disease, sickle-cell anemia.

The thalasassemias 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.

Alpha thalassemias

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 childhoood or in early adult life, when the anemia and
splenomegaly is 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 middle microcytic hypochomic anemia. There is a high prevalence (about
30%) of deletion of one of the two &globin; loci on chromosomes of people of
recent African origin, and so the inheritance of two such chormosomes 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

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.

Thre 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 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 are weakness and fatigue.

Thalassemia 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.