The thalassemias are a diverse group of inherited disorders in which the rate of production of certain hemoglobins is decreased leading to an imbalance of globin chains available for hemoglobin dimer construction. This results in the formation of abnormal amounts of structurally normal (normal amino acid sequence) hemoglobins.

For instance, if inadequate numbers of ß-chains were synthesized, a-chains would be in relative excess.

The excess a-chains combine with other available globin chains (d or g) to form increased amounts of Hgb A2 (a2 d2) and Hgb F ( a2 g 2) or Hgb Barts (g4).

Remember, the globin chain (a , b , d , e , g , and z) structural genes are located on chromosome 16 (a ; z) and chromosome 11 (b ; d ; e ; g).

Note that there are two a gene alleles on each chromosome 16 or four a genes per cell. In contrast, there is only one ß gene allele on each chromosome 11 or two ß genes per cell. Interestingly there are two g gene alleles on each chromosome 11 or four g genes per cell.

Normally all four a genes and both ß genes are active in the production of globin chains.

In ß thalassemia synthesis of the ß chain is defective. In a thalassemia, it is synthesis of the a chain that is defective.

Both the alpha and beta chains are structurally normal. The defect is quantitative!

ß -thalassemia is common in the Mediterranean region, and in portions of Africa, Asia, the South Pacific, and India.

a -thalassemia is most common in Southeast Asia.

Knowledge of the ethnic background of the patient may be helpful when thalassemia is in the differential diagnosis.

ß-Thalassemia

In both a - and ß- thalassemia inadequate amounts of hemoglobin are made which often results in the production of red cells that are microcytic and hypochromic.

We will look first at the more readily recognized ß-thalassemia.

In ß-thalassemia point mutations or a partial deletions of chromosome 11 cause defective synthesis of the ß chain. Over 100 mutations have been identified.

Mutations in the promoter affect transcription. Mutations in the coding regions, splice sites, or termination codons affect RNA processing and translation.

Normally a and b globin chains are made in roughly equal amounts.

When ß-globin chains are in short supply or absent, as in ß-thalassemia, a-chains are in excess. The excess a-chains combine with other available ß-family globin chains ( d or g) to form increased amounts of Hgb A2 (a2 d2) and Hgb F (a2 g 2).

Hgb Barts ( g 4) or tetramers of excess gamma chains may also form.

The clinical severity of ß-thalassemia depends on the degree to which production of the ß-chain is inadequate.

The mutated ß gene is designated with a + sign or ß+.

In ß-thalassemia major no ß chains (ßo) or very little is made (ß+).

In ß-thalassemia minor ß+ chains are made in mildly reduced amounts.

In ß+thalassemia intermedia ß+ chains are made in amounts intermediate to the major and minor forms.

Signifcance of ß-gene Mutation

type 1 ß+ the defect results in about 10%
of normal ß chain production

type 2 ß+ the defect results in about 50%
of normal ß chain production

type 3 ß+ the defect results in >50%
of normal ß chain production

In ß-thalassemia major (Cooley's anemia) no ß chains (homozygous for ßo) or very little ß chain (homozygous for ß+) is made.

Clinical manifestations are not seen

until about six months of life when globin production would normally change from predominantly g -chain to ß-chain.

Beginning in the first year of life the

PBS shows severe anisocytosis and poikilocytosis, targets, elliptocytes, teardrops, and NRBCs.

Hgb electrophoresis shows increased Hgb F, increased Hgb A2, and variable amounts of Hgb A.

ß-thalassemia major patients have severe, transfusion dependent anemia. Nearly all patients have hepatomegaly and splenomegaly.

Expansion of the marrow by erythroid hyperplasia causes enlargement of bones. The life span of patients with ß-thalassemia major is short, most dying before adulthood.

Ironover load, secondary to transfusion dependency, results in damage to the heart, liver and endocrine organs.

ß-thalassemia major is most common in Mediterranean, Arabic, and Southeast Asian peoples.

In ß-thalassemia trait (aka ß-thalassemia minor) defective ß-chain synthesis results in mildly reduced production of ß+ chains and thus, a mild excess of a globin chains. The excess a globin chains denature, causing damage to young red cells, leading to red cell death in the marrow (ineffective erythropoiesis) or decreased survival in the peripheral blood.

The RBCs are microcytic and hypochromic; often with associated erythrocytosis. The anemia is usually mild.

High Hemoglobin A2 levels are classic for ß-thalassemia trait. Hemoglobin F levels are mildly increased.

People with ß-thalassemia trait are heterozygous for either bo or for ß+.

If both parents have ß--thalassemia trait their offspring have a 25% chance of being normal; a 50% chance of having ß-thalassemia trait; and a 25% chance of having ß-thalassemia major.

In thalassemia minor, the severity of disease expression may only be seen as mild anemia and a microcytic state.

It thus may be difficult to distinguish from iron deficiency.

Differentiating features include the following: Thalassemias are more apt to demonstrate reticulocytosis and basophilic stippling in the peripheral blood.

In ß-thalassemia intermedia ß+ chains are made in amounts intermediate to the major and minor forms.

People with ß-thalassemia intermedia may be homozygous for type 2 ß+ and type 3 ß+ (production of 50% or more ß chain).

Signifcance of ß-gene Mutation

type 1 ß+ the defect results in about 10%
of normal ß chain production

type 2 ß+ the defect results in about 50%
of normal ß chain production

type 3 ß+ the defect results in >50%
of normal ß chain production

In a -thalassemia, ß-chains without a -chains, form pairs and combine to form hemoglobin H (ß4).

In addition, unpaired ß globin chains may precipitate, damaging the RBC membrane.

a-Thalassemia

in classical a -thalassemia the defect is caused by the deletion from chromosome 16 of entire a-genes.

Less common causes of a -gene translation disorders are point mutations, ie. Hgb Constant Spring (mutation of a -chain termination codon causes addition of 31 extra amino acids, resulting in an unstable globin).

One to four a -genes may be deleted in the a -thalassemia disorders.

The clinical manifestations of a -thalassemia vary with the number of alpha-chain genes that are deleted from chromosome 16.

If only one alpha gene is deleted, no hematologic abnormalities are seen. This is known as a silent carrier state.

If two alpha genes are deleted, either homozygous (a-/a-) or heterozygous ( - - /aa), the condition is a -thalassemia trait.

The heterozygous type is encountered in Southeast Asian populations, but is rare in Afro-Americans.

a-thalassemia trait results in microcytosis, hypochromia, and mild anemia. Hemoglobin A2 levels are normal.

Would you expect to see an abnormal Hgb at birth?

If three alpha genes are deleted ( - - /-a) hemoglobin H is produced. Hemoglobin H (four ß chains) is unstable and precipitates in vivo causing hemolysis. The hemolysis is usually compensated.

In Hgb H disease the RBCs are microcytic and hypochromic with target cells. Crystal violet or new methylene blue supravital stains will detect Heinz bodies (precipitated Hgb H).

Rarely, point mutations are the cause of a -gene translation disorders, ie. Hgb Constant Spring (mutation of a -chain termination codon causes addition of 31 extra amino acids, resulting in an unstable globin).

There exist other disorders of Hgb production with clinical findings similar to the thalassemias.

In delta-beta thalassemia production of ß and d globin chains is decreased.

In hemoglobin Lepore an erroneous cross between ß and d genes produces an abnormal fusion protein ßd. No normal ß or d chains are produced and the fusion protein Hgb ßd is inefficently produced.

Thalassemia

Hemoglobin E is sometimes referred to as one of the thalassemic disorders because patients with Hemoglobin E (glutamine Æ Iysine at position 26) have clinical features and a PBS morphology similar to ß-thalassemia trait.

Hemoglobin E is common in people of Southeast Asian ancestry.

When Hgb E is combined with ß-thalassemia trait, splenomegaly as well as anemia is present.