thalassemia

thalassemia, group of blood disorders characterized by a deficiency of hemoglobin, the blood protein that transports oxygen to the tissues. Thalassemia (Greek: “sea blood”) is so called because it was first discovered among peoples around the Mediterranean Sea, among whom its incidence is high. Thalassemia genes are widely distributed in the world but are found most often among people with ancestors from the Mediterranean, the Middle East, and southern Asia. Thalassemia has also been found in some northern Europeans and Native Americans. Among persons of African descent the disease is unusually mild. It is thought that the potentially lethal thalassemia gene is retained in certain populations because it provides some protection from malaria in the heterozygous state.

Genetic defects of thalassemia

Hemoglobin is composed of a porphyrin compound (heme) and globin. Thalassemia is caused by genetically determined abnormalities in the synthesis of one or more of the polypeptide chains of globin. The various forms of the disorder are distinguished by different combinations of three variables: the particular polypeptide chain or chains that are affected; whether the affected chains are synthesized in sharply reduced quantities or not synthesized at all; and whether the disorder is inherited from one parent (heterozygous) or from both parents (homozygous).

The five different polypeptide chains are: alpha, α; beta, β; gamma, γ; delta, δ; and epsilon, ε. No thalassemic disorder is known to involve the ε-chain. Involvement of the γ-chain or δ-chain is rare. Of the 19 variations of thalassemic inheritance, a few (such as the two heterozygous α-thalassemias) are benign and generally exhibit no clinical symptoms. Other forms exhibit mild anemia, while the most severe form (homozygous α-thalassemia) usually causes premature birth, either stillborn or with death following within a few hours. It is thought that a primary thalassemia genetic mutation results in reduction in the rate at which α-, β-, or δ-chains are manufactured, the chains being otherwise normal. The relative deficiency of one pair of chains and the resultant imbalance of chain pairs result in ineffective production of red blood cells, deficient hemoglobin production, microcytosis (small cells), and destruction of red cells (hemolysis).

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When defects occur in both δ- and β-chain synthesis, causing δ-β-thalassemia, the concentrations of a type of hemoglobin known as Hb F usually are considerably elevated since the number of β-chains available to combine with α-chains is limited and γ-chain synthesis is not impaired. Beta-thalassemia constitutes the majority of all thalassemias. A number of genetic mechanisms account for impaired production of β-chains, all of which result in inadequate supplies of messenger RNA (mRNA) available for proper synthesis of the β-chain at the ribosome (the protein-synthesizing organelle within cells). In some cases no mRNA is produced. Most defects have to do with production and processing of the RNA from the β-gene. In α-thalassemia, by contrast, the gene itself is deleted. There are normally two pairs of α-genes, and the severity of the anemia is determined by the number deleted. Since all normal hemoglobins contain α-chains, there is no increase in Hb F or Hb A₁ (normal adult hemoglobin). The extra non-α-chains may combine into tetramers to form β₄ (hemoglobin H) or γ₄ (hemoglobin Bart). These tetramers are ineffective in delivering oxygen and are unstable. Inheritance of deficiency of a pair of genes from both parents results in intrauterine fetal death or severe disease of the newborn.

Clinical characteristics of thalassemia

The red cells in this condition are unusually flat with central staining areas and for this reason have been called target cells. In the mild form of the disease, thalassemia minor (heterozygous β-thalassemia), there is usually only slight or no anemia, and life expectancy is normal. Occasionally, complications occur involving slight enlargement of the spleen. Thalassemia major (homozygous β-thalassemia, or Cooley anemia) is characterized by severe anemia, enlargement of the spleen, and body deformities associated with expansion of the bone marrow. The latter presumably represents a response to the need for greatly accelerated red cell production by genetically defective red cell precursors, which are relatively ineffective in producing mature red cells. Clinical characteristics of thalassemia major, including anemia, an enlarged spleen, and often an enlarged liver, appear a few months following birth. Infections commonly develop. At about the age of four years, stunted physical growth becomes apparent. Many patients develop a typically protruding upper jaw, prominent cheekbones, and marrow expansion in the long bones, ribs, or vertebrae, which fracture easily.

Treatment of thalassemia major involves blood transfusions. However, they are of only temporary value and lead to excessive iron in the tissues once the transfused red cells break down. The enlarged spleen may further aggravate the anemia by pooling and trapping the circulating red cells. Splenectomy may partially relieve the anemia but does not cure the disease. In 2023 the U.S. Food and Drug administration approved a treatment for β-thalassemia known as Casgevy, which employs CRISPR gene-editing technology to disrupt a gene that represses normal hemoglobin production. The therapy entails extraction of stem cells from the patient’s bone marrow. The cells are then treated with Casgevy in a laboratory and infused back into the patient to reestablish hemoglobin production. The effects of the treatment are potentially lifelong.