Thalassemia
Questions Received:
Responses:
What does it mean to have a high A2 in your hemoglobin? My daughter just had a blood test to figure out her blood type and the lab test indicates a high level of A2 in relation to a normal A1? what are the implications?
26th April 1999
If the concetration of A2 is increased in haemoglobin, this is usually evidence of a condition known as beta-thalassemia (b -thalassemia). The name thalassemia is derived from the Greek word thalassa, for sea, reminding us that this condition was first described in people living around the Mediterranean Sea. Now we know that thalassemias are widely distributed across the world, and may have evolved originally as a partial protection against malaria.
The red cells in the blood are filled with haemoglobin molecules - about 280 million of them in each cell - and their job is to carry oxygen to the body cells and carbon dioxide away from the cells. Each haemoglobin molecule is built from 4 protein units called globin and 4 haeme groups which contain iron. (Diagram) Even apparently small changes in this arrangement can affect the way the molecule works, and give rise to clinical problems. A normal haemoglobin molecule contains two alpha globins and two beta globins to make up the complement of 4 globins. The information from which these building blocks are assembled is stored as genes on chromosomes 16 and 11. Usually, the synthesis of alpha and beta globins is very tightly coordinated to produce almost equal numbers of each. Specific enzymes break down any excess globin chains of one sort or the other that may arise. In the case of beta-thalassemia there is a problem in the manufacture of beta globin with the result that the haemoglobin molecules contain more alpha globin than beta globin.
The implications will depend on how many unmatched alpha globin chains are being produced, and the symptoms can range from none to severe (Schrier 1994). The formation of red cells in the bone marrow can be affected, accompanied by different degrees of anaemia. Bone disease may be associated with thalassemia, but there is evidence that this complication can be prevented by regular screening and treatment (Vichinsky, 1998).
The more severe forms of thalassemia are currently treated by regular blood transfusions, but this can create an iron imbalance. Bone marrow transplantation is an option for a few patients. A growing insight into the molecular genetics of thalassemia is giving hope that suitable treatments can be found. The two main research avenues at present are to reactivate the fetal form of haemoglobin or use gene therapy (Stamatoyannopoulos, 1992; Dover, 1998; Ginder et al, 1998; Olivieri and Weatherall, 1998; Pawliuk et al, 1998).
References
Dover, G.J. (1998) Hemoglobin switching protocols in thalassemia. Experience with sodium phenylbutyrate and hydroxyurea. Annals of the New York Academy of Science, 850, 80-86 (Jun 30).
Ginder, G.D., Singal, R., Little, J.A., Dempsey, N., Ferris, R., and Wang, S.Z. (1998) Silencing and activation of embryonic globin gene expression. Annals of the New York Academy of Science, 850, 70-79 (Jun 30).
Olivieri, N.F., and Weatherall, D.J. (1998) The therapeutic reactivation of fetal haemoglobin. Human Molecular Genetics, 7(10), 1655-1658.
Pawliuk, R., Bachelot, T., Raftopoulos, H., Kalberer, C., Humphries, R.K., Bank, A., and Leboulch, P. (1998) Retroviral vectors aimed at the gene therapy of human beta-globin gene disorders. Annals of the New York Academy of Science, 850, 151-162 (Jun 30).
Schrier, S.L. (1994) Thalassemia: pathophysiology of red cell changes. Annual Review of Medicine, 45, 211-218.
Stamatoyannopoulos, J.A. (1992) Future prospects for treatment of hemoglobinopathies. Western Journal of Medicine, 157(6), 631-636 (Dec).
Vichinsky, E.P. (1998) The morbidity of bone disease in thalassemia. Annals of the New York Academy of Science, 850, 344-348 (Jun 30).
Are there any specific blood disorders associated with people of Greek ancestry?
21st May 1999
We are not aware of any blood disorders found only in Greek people. There is however a significant disorder called beta-thalassaemia which affects people in countries around the Mediterranean, including Greece.
Beta-thalassaemia is expressed across a spectrum of severity from relatively inconsequential effects to severe anaemia requiring regular blood transfusions (Kulozik, 1991). The synthesis of beta-globin - one of the components of normal haemoglobin molecules - is reduced or absent in people with beta-thalassaemia with the result that there is a relative excess of alpha-globin chains and abnormalities in the formation of red blood cells. Many different mutations of the beta-globin gene are possible and these can interfere with gene expression at any point from transcription of the gene to the assembly of haemoglobin molecules. The clinical picture is largely determined by the type of mutation.
Reference
Kulozik, A.E. (1991) Beta thalassemia: molecular pathogenesis and clinical variability. Klin Padiatr, 203(4), 276-283 (Jul-Aug).
What is Beta Thalassemia, and how can it affect someone’s life? Can this develop into Thalassemia major? Are there any symtoms ie: stomach complaints or fatigue?
13th June 1999
Thalassaemia is an inherited disorder of the blood. Because of genetic errors, the affected person has difficulty making haemoglobin. Haemoglobin is the molecule that gives red blood cells their colour and enables them to carry the gases oxygen and carbon dioxide around the body - oxygen is carried to the cells where it is used for metabolism, and carbon dioxide is carried away from the cells as a by-product of metabolism. The main problem with thalassemia is a reduction in the amount of globin being formed, and thus potentially a diminished ability of the blood to transport gases around the body. The effect on someone’s life will depend on the type and degree of thalassaemia.
Haemoglobin is a complex molecule which has four chains of amino acids known as globin chains and an iron-containing haeme group attached to each. Each tiny red cell in the blood contains about 280 million molecules of haemoglobin. Usually the globin chains consist of two alpha chains and two others which are different. Most adults have what is known as type A1 hemoglobin, which contains two alpha and two beta globin chains. The remaining 10% or so have type A2 haemoglobin, with two alpha and two delta chains. (Babies are born with a slightly different type of haemoglobin called fetal hemoglobin which has two alpha chains and two gamma chains. This is gradually replaced with the adult form of haemoglobin as the child develops.) If the body fails to produce enough of one type of globin chain then insufficient haemoglobin is made and the person becomes anaemic.
There are different degrees and types of thalassaemia. The genetic basis for each is established at the time of conception, so it is not possible for thalassaemia of one type to transform into another type during the person’s lifespan. Beta-thalassaemia is generally the most common type, although there are differences from population to population. It is due to an abnormality (or abnormalities) in one or both of the genes which specify beta globin. If both the beta globin genes are abnormal, or even absent, then the person will be unable to manufacture beta globin in their bone marrow and therefore they will not be able to make haemoglobin A1. This is called beta-thalassaemia major, and is the most serious form of beta-thalassaemia. Instead they will make one of the other forms of haemoglobin such as A2 or fetal hemoglobin to try and compensate for the deficiency of beta globin. However, these alternative forms of haemoglobin are less effective postnatally than the type A1. Usually, severe anaemia develops a few months after birth. Because of the difficulty in making haemoglobin, the bone marrow proliferates and the bones containing the marrow may become distorted. This may be especially noticeable with the facial bones. The spleen enlarges because it has to remove a larger number of abnormal red cells from the circulation. Frequent blood transfusions will be required in severe cases - this can be a life-threatening condition.
If only one of the beta globin genes is affected, the person has a milder form of anaemia called beta-thalassaemia minor. There may be no obvious symptoms at all, or there may be mild symptoms such as fatigue that can be traced to the presence of mild anaemia. There may be slight but painless enlargement of the spleen. Treatment may not be required, but genetic counselling of couples is helpful to evaluate the risk of passing on the trait to the next generation.
Further information about thalassaemia can be found at the website of The Joint Center for Sickle Cell and Thalassemia: www.cancer.mgh.harvard.edu/sickle.htm