Thalassemia

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Thalassemia is a type of anemia in the group of hereditary anemias. This genetic condition confers resistance to malaria, but causes decreased synthesis of one or more of the hemoglobin polypeptide chains. There are several genetic types, with clinical pictures ranging from hardly detectable hematological abnormalities to severe anemia and pictures of terminal disease.

Name

It comes from the Greek θάλασσα: 'sea', and αἷμα: 'blood'. Literally, it would be 'marine blood', but in reality the term refers to the Mediterranean Sea, since the disease is more frequent in this area. For this reason, it is sometimes also called Mediterranean anemia.

Prevalence

It is estimated that 5% of the world population carries a mutated gene for hemoglobin (being a carrier of thalassemia more frequent than any other hemoglobinopathy). Some 300,000 children are born each year with thalassemia syndromes worldwide. Thalassemia is very common in Mediterranean areas such as North Africa, southern Spain and Italy, regions of Sicily, Calabria, Apulia and Sardinia. In these last two regions there are more than 700,000 carriers in a total population of just under 7 million.

Description

Thalassemia is a group of broad-spectrum diseases. These range from simple asymptomatic abnormalities in the blood count to severe and fatal anemia. Adult hemoglobin, called Hemoglobin A, is composed of the union of four polypeptide chains: two alpha (α) chains and two beta (β) chains. There are two copies of the gene that produces α hemoglobin (HBA1 and HBA2), each encoding an α-chain, and both genes are located on chromosome 16. The gene encoding β chains (HBB) is located on chromosome eleven.

It is an inherited form of anemia in which the synthesis of one or more of the four globin chains is reduced, usually the two α and the two β chains, which are part of the hemoglobin in the red blood cells of the blood. The function of hemoglobin is to carry oxygen from the lungs to the body tissues. In anemia this function is insufficient to meet the needs of the tissues (for example, the muscles and the brain). The word thalassemia comes from the Greek and means sea. This disorder was so named because it is more common in people of Mediterranean origin. However, its distribution is worldwide. There are different types: the main forms are those of the adult called α or β thalassemia depending on whether the α or β chain genes are altered. Its severity varies according to genetic makeup. It is the most common inherited blood disease and, in turn, is the most common caused by an abnormality in a single gene.

In thalassemia, the structure of both hemoglobin chains remain intact, but the α or β chain is absent or exists in small amounts, due to abnormalities in the genes that code for these proteins. This causes an imbalance in the amount of globin in the predominantly α or β chains. The chains precipitate in the absence of sufficient other chains with which to bind, and this precipitation interferes with the formation of red blood cells. Fewer red blood cells than normal are produced and those that are able to develop include the precipitated hemoglobin chains inside them, so that they cannot pass through the capillaries and are destroyed prematurely. This causes severe anemia and to compensate for it, the bone marrow hyperplasia trying to produce enough red blood cells, and the spleen also enlarges. Severe deformities in the skull and long bones are also possible.

In the α-thalassemia gene HBA1 (OMIM 141800) and HBA2 (OMIM 141850), there is a deficiency in the synthesis of α chains. The result is an excess of β chains that poorly transport oxygen, leading to low O₂ concentrations (hypoxemia). In parallel, in β-thalassemia (OMIM 141900) there is a lack of β chains, and the consequent excess of alpha chains can form insoluble aggregates that adhere to the erythrocyte membrane, potentially causing death. of these and their precursors, causing anemia of the hemolytic type.

Molecular causes of disease

Image of unbalanced crossroads.

This disease is caused by deletions in one or several genes that make up the α-globin and β-globin groups. Depending on whether these deletions involve more or fewer genes, the type of thalassemia will be more or less severe.

These deletions cause a decrease in the production of α or β chains, depending on the place of deletion; An attempt is made to compensate for the shortage of α chains with an increase in the production of β chains, and vice versa, which leads to the formation of unstable hemoglobins that cause the destruction of red blood cells and therefore anemia.

The deletions in turn appear to be the result of unbalanced crossovers between the duplicated segments present in the cluster region.

In the case of β-thalassemias, in addition to the deletion of the β-globin gene, they can also occur due to other causes such as:

Mutations in the promoter that stop or reduce your transcript.
Mutations on cutting and splice sites that prevent the removal of introns.
Mutations on the poly-A acceptor site that affect mRNA processing.
Changes in the reading pattern.

Symptoms

A gene defect or deletion in β-thalassemia causes mild to moderate hemolytic anemia without any symptoms. The deletion of two genes cause more severe anemia and the presence of symptoms: weakness, fatigue, respiratory distress. In the more serious variants, such as beta thalassemia major, jaundice, skin ulcers, gallstones, and an enlarged spleen (sometimes even enormous) may occur. Excessive activity of the bone marrow can cause the widening and enlargement of some bones, especially those of the head and face.

Long bones tend to become weak and break easily. Children with certain thalassemias may grow more slowly and reach puberty later than normal. As iron absorption may increase in response to anemia coupled with the requirement for frequent blood transfusions (which supply more iron), excessive amounts of iron may accumulate and be deposited in the heart musculature, causing heart failure.

Thalassemias are more difficult to diagnose than other hemoglobin disorders. Analysis of a drop of blood by electrophoresis can be helpful but not conclusive, especially in the case of alpha thalassemia. Therefore, the diagnosis is usually based on hereditary patterns and special hemoglobin tests. People with thalassemia usually do not require any treatment, but those with severe variants may require a bone marrow transplant. Gene therapy is in the investigational phase.

Advantage of having alpha thalassemia

As occurs in the best-known case of sickle cell anemia, α-thalassemia also protects individuals who carry it against malaria. Malaria or paludism is produced by a protista parasite of the genus Plasmodium and is transmitted by a mosquito of the genus Anopheles. Protection against this disease by individuals with α-thalassemia is due to the fact that Plasmodium is only capable of parasitizing healthy erythrocytes. However, the blood of someone with this type of anemia presents a high number of deformed erythrocytes because the hemoglobin is not well constituted and this is essential since it leaves the parasite defenseless in the blood allowing our immune system to kill it.

Heterozygous advantage occurs when an allele that is deleterious in its homozygous form is, instead, advantageous in its heterozygous form. This phenomenon is what is called balanced polymorphism. It means that the negative selection of the allele in the homozygous state is balanced by the positive selection in favor of the allele in the heterozygous state.

Because of this, there is a high frequency of thalassemias, and in general of hemoglobinopathies in countries with endemic malaria, so that the geographic distribution of malaria correlates with that of thalassemias.

Classification

α Talasemia trait (porter). The mutations of the α chain in chromosome 16 affect one of the genes of a chromosome causing a silent (asymptomatic) thalassemia characterized by some hemoglobines with three β and a α globine. The carriers may have α-chain mutations in two chromosomes (16) affecting a genes of each chromosome (or the two genes of one chromosome, the two of the homologous chromosome being normal) causing a mild thalasemia (can be asymptomatic) characterized by hemoglobines with three β and a α globine. Because there are enough genes without mutation in the α chain, most hemoglobin molecules have the respective two α and two β chains. Most carriers of α thalassemia do not know and are discovered with DNA analysis and molecular biology.

α Serious Talasemia (Hemoglobin H). The mutations of the α chain in chromosome 16 affect three of the genes (involving both homologous chromosomes) causing a severe thalassemia characterized by most hemoglobines with three β chains and a α globine. Those affected have intravascular hemolysis causing severe anemia with the most intense symptoms.

greater Thalasemia (Bart disease). The mutations of the α chain in chromosome 16 affect the four genes (involving both homologous chromosomes) causing a fetal hydropes characterized by hemoglobins with only four γ (gamma) chains and is incompatible with life.
β⁺ Less Thalasemia (Minor). The β-chain mutations in chromosome 11 affect one of the genes causing a relatively mild thalassemia characterized by a hemoglobin with three α and a β-globin. There may be no symptoms like symptoms may be between mild and severe.

Hemoglobin H disease It is suffered by those individuals who only possess a functional copy of the α-globin gene. It leads to a moderate anemia with inclusions in the erythrocytes produced by hemoglobin H, which is made up of four β-globin chains, due to the few that are of the other type. Clinical manifestations are from mild to moderate anemia, sometimes it can lead to splenomegaly.

βo Talasemia Mayor (Major) or Cooley Anemia. Mutations of the β chain in chromosome 11 affect both genes causing the most severe thalassemia characterized by the total lack of β globine. Four α chains are combined in default of the β chains forming an unstable hemoglobin that tends to precipitate in the red blood cells causing damage to the cell membrane and increasing the fragility of the hematie in question. Because of the massive spleen-directed hemolisis, the symptoms are more severe: paleness, susceptibility to infections, bone fragility, jaundice, iron deposits in the liver and heart, and may not live long.

Diagnosis

Tests done to find out if an individual has any of the types of thalassemia are blood tests, which look at the shape and number of red blood cells in the blood. Another way to diagnose the disease is through genetic studies. Which give us exact information on the type of thalassemia and its cause.

Treatment

Blood transfusions: is the treatment used for the most severe types of thalassemia, such as β-talasemia. Individuals who possess it need transfusions regularly, every 2 or 3 weeks, they help keep hemoglobin at almost normal levels and prevent other complications, such as heart failure and bone deformities. There are patients of other less severe thalassemias that require these blood transfusions only occasionally or because they develop a vira disease or other infections, which may cause anemia to become more serious.

Folic acid supplement: in the event that the affected individual only suffers anemia what is supplied is folic acid, as for other types of anemias.

Use of iron kine: repeated blood transfusions can result in the accumulation of iron in the body. This accumulation can be harmful to the heart, liver, and other organs. To prevent these damages, individuals who are subjected to transfusions regularly receive treatment with a type of medication called iron kine, deferoxamine is currently used. This is what it does to fix iron and in that way the organism is helped to get rid of the excess of it. The amount of iron that an individual has in blood is measured by blood tests, the problem is that iron levels in the heart and liver are not too accurately measured, so a biopsy must be used. That's why most of the patients with severe thalassemias who die are due to that iron cluster.

Bone marrow transplant: it is curative treatment. This method is effective when the donor is perfectly genetically compatible, the most compatible are family members, such as a brother of the affected individual. With the marrow transplant it is possible to cure 85% of individuals who get a compatible donor. However, only 30% of patients with thalassemia get a family member who is in a position to be a donor. The procedure is risky and can lead to the patient's death. It is also currently being used for the cure of this anemia and others the blood of the umbilical cord of a newborn brother and is being as effective as bone marrow transplant. Like the bone marrow, the cord blood has indifferentiated cells, which is called stem cells that produce all other blood cells. As an example of this last method is the case of the Sevillian child who suffered from greater beta thalassemia and that thanks to the blood of the umbilical cord of his newborn brother has been healed. That brother to be a fully child-friendly donor has been genetically selected, being the first baby whose gestation and genetic treatment process has taken place entirely in Spain.

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