Thalassemia

What is Thalassemia?

Thalassemia (from θάλασσα, thalassa, sea + αἷμα, haima, blood; British spelling, "thalassaemia") is an inherited autosomal co-dominant blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting symptom of the thalassemias.

Thalassemia is a quantitative problem of too few globins synthesized, whereas sickle-cell anemia (a hemoglobinopathy) is a qualitative problem of synthesis of an incorrectly functioning globin. Thalassemias usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. Hemoglobinopathies imply structural abnormalities in the globin proteins themselves. The two conditions may overlap, however, since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some thalassemias are hemoglobinopathies, but most are not. Either or both of these conditions may cause anemia.

The disease is particularly prevalent among Mediterranean people, and this geographical association was responsible for its naming: ''Thalassa (θάλασσα)'' is Greek for the sea, ''Haema (αἷμα)'' is Greek for blood. In Europe, the highest concentrations of the disease are found in Greece and in parts of Italy, in particular, Southern Italy and the lower Po valley. The major Mediterranean islands (except the Balearics) such as Sicily, Sardinia, Malta, Corsica, Cyprus and Crete are heavily affected in particular. Other Mediterranean people, as well as those in the vicinity of the Mediterranean, also have high rates of thalassemia, including Middle Easterners and North Africans. Far from the Mediterranean, South Asians are also affected, with the world's highest concentration of carriers (18% of the population) being in the Maldives.

Recently, increasing reports suggest that up to 5% of patients with beta-thalassemias produce fetal hemoglobin (HbF), and use of hydroxyurea also has a tendency to increase the production of HbF, by as yet unexplained mechanisms.

Giving a happy ending to a poignant family tale and raising fresh hope of leveraging stem cell therapy, a group of doctors and specialists in Chennai and Coimbatore have registered the first successful treatment of thalassaemia in a child using a sibling's umbilical cord blood.

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Thalassemia Genetic Prevalence

α and β thalassemia are often inherited in an autosomal recessive fashion although this is not always the case. Cases of dominantly inherited α and β thalassemias have been reported, the first of which was in an Irish family who had a two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β-globin gene. For the autosomal recessive forms of the disease 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.

There are an estimated 60-80 million people in the world who carry the beta thalassemia trait alone. This is a very rough estimate and the actual number of thalassemia Major patients is unknown due to the prevalence of thalassemia in less developed countries in the Middle East and Asia where genetic screening resources are limited. Countries such as India, Pakistan and Iran are seeing a large increase of thalassemia patients due to lack of genetic counseling and screening. There is growing concern that thalassemia may become a very serious problem in the next 50 years, one that will burden the world's blood bank supplies and the health system in general. There are an estimated 1,000 people living with Thalassemia Major in the United States and an unknown number of carriers. Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult.

As with other genetically acquired disorders, genetic counseling is recommended.

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Thalassemia Prevalence

Generally, thalassemias are prevalent in populations that evolved in humid climates where malaria was endemic. It affects all races, as thalassemias protected these people from malaria due to the blood cells' easy degradation. Thalassemias are particularly associated with people of Mediterranean origin, Arabs, and Asians. The Maldives has the highest incidence of Thalassemia in the world with a

carrier rate of 18% of the population. The estimated prevalence is 16% in people from Cyprus, 1% in Thailand, and 3-8% in populations from Bangladesh, China, India, Malaysia and Pakistan. There are also prevalences in descendants of people from Latin America and Mediterranean countries (e.g. Greece, Italy, Portugal, Spain, and others). A very low prevalence has been reported from people in Northern Europe (0.1%) and Africa (0.9%), with those in North Africa having the highest prevalence. Ancient Egyptians suffered from Thalassemia with as many as 40% of studied predynastic and dynastic mummies with the genetic defect. Today, it is particularly common in populations of indigenous ethnic minorities of Upper Egypt such as the Beja, Hadendoa, Saiddi and also peoples of the Delta, Red Sea Hill Region and especially amongst the Siwans.

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Thalassemia Pathophysiology

The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected.

Thalassemia produces a ''deficiency'' of α or β globin, unlike sickle-cell disease which produces a specific mutant form of β globin.

β globin chains are encoded by a single gene on chromosome 11; α globin chains are encoded by two closely linked genes on chromosome 16. Thus in a normal person with two copies of each chromosome, there are two loci encoding the β chain, and four loci encoding the α chain. Deletion of one of the α loci has a high prevalence in people of African or Asian descent, making them more likely to develop α thalassemias. β thalassemias are common in Africans, but also in Greeks and Italians.

Alpha (α) thalassemias

The α thalassemias involve the genes HBA1 and HBA2, inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome. α thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves.

Beta (β) thalassemias

Beta thalassemias are due to mutations in the HBB gene on chromosome 11, also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as (βo) if they prevent any formation of β chains (which is the most severe form of beta Thalassemia); they are characterized as (β+) if they allow some β chain formation to occur. In either case there is a relative excess of α chains, but these do not form tetramers: rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates.

Delta (δ) thalassemia

As well as alpha and beta chains being present in hemoglobin about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations can occur which affect the ability of this gene to produce delta chains.

In combination with other hemoglobinopathies

Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:

  • hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically similar to β thalassemia major or thalassemia intermedia.
  • 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.

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Thalassemia Treatment

Patients with thalassemia minor usually do not require any specific treatment. Treatment for patients with thalassemia major includes chronic blood transfusion therapy, iron chelation, splenectomy, and allogeneic hematopoietic transplantation.

Medication

Medical therapy for beta thalassemia primarily involves iron chelation. Deferoxamine is the intravenously administered chelation agent currently approved for use in the United States. Deferasirox (Exjade) is an oral iron chelation drug also approved in the US in 2005.

The antioxidant indicaxanthin, found in beets, in a spectrophotometric study showed that indicaxanthin can reduce perferryl-Hb generated in solution from met-Hb and hydrogen peroxide, more effectively than either Trolox or Vitamin C. Collectively, results demonstrate that indicaxanthin can be incorporated into the redox machinery of β-thalassemic RBC and defend the cell from oxidation, possibly interfering with perferryl-Hb, a reactive intermediate in the hydroperoxide-dependent Hb degradation.

Carrier detection

  • A screening policy exists in 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.
  • In Iran as a premarital screening, the man's red cell indices are checked first, if he has microcytosis (mean cell haemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic their haemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassaemia trait) they are referred to the local designated health post for genetic counseling.

In 2008, in Spain, a baby was selectively implanted in order to be a cure for his brother's thalassemia. The child was born from an embryo screened to be free of the disease before implantation with In vitro fertilization. The baby's supply of immunocompatible cord blood was saved for transplantation to his brother. The transplantation was considered successful.

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Thalassemia Benefits

Being a carrier of the disease may confer a degree of protection against malaria, and is quite common among people from Italian or Greek origin, and also in some African and Indian regions.

This is probably by making the red blood cells ''more'' susceptible to the less lethal species ''Plasmodium vivax'', simultaneously making the host RBC environment unsuitable for the merozoites of the lethal strain ''Plasmodium falciparum''. This is believed to be a selective survival advantage for patients with the various thalassemia traits. In that respect it resembles another genetic disorder, sickle-cell disease.

Epidemiological evidence from Kenya suggests another reason: protection against severe anemia may be the advantage.

People diagnosed with heterozygous (carrier) Beta-Thalassemia have some protection against coronary heart disease.

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