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Encyclopedia > Thalassemia
Thalassemia
Classification & external resources
MedlinePlus 000587
eMedicine ped/2229  radio/686

Thalassemia (British spelling, "thalassaemia") is an inherited autosomal recessive 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 causes the formation of abnormal hemoglobin molecules, and this in turn causes the anemia which is the characteristic presenting symptom of the thalassemias. MedlinePlus (medlineplus. ... eMedicine is an online clinical medical knowledge base that was founded in 1996. ... In genetics, the term recessive gene refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele). ... Blood diseases affect the production of blood and its components, such as blood cells, hemoglobin, blood proteins, the mechanism of coagulation, etc. ... Structure of hemoglobin. ... This article discusses the medical condition. ...


Thalassemia is a class of hemoglobinopathies, like sickle-cell disease. Thalassemias result in under production of globin proteins, often through mutations in regulatory genes. Hemoglobinopathies imply structural abnormalities in the globin proteins themselves [1]. The two conditions may overlap, however, since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Either or both of these conditions may cause anemia. Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. ... Sickle-cell disease is a group of genetic disorders caused by sickle hemoglobin (Hgb S or Hb S). ...


The disease is particularly prevalent among Mediterranean peoples, and this geographical association was responsible for its naming: Thalassa (θάλασσα) is Greek for the sea, Haema (αίμα) is Greek for blood. Thalassa, personification of the Mediterranean sea. ...


There is no cure for thalassemias, and the best treatment available today consists of frequent blood transfusions (every two to three weeks) with iron chelation therapy (e.g. deferoxamine) administered subcutaneously. Bone marrow transplants (hematopoietic stem cell transplantations) and cord blood transplantation with pre-operative myeloablation are potentially curative, though the latter requires further investigation. Blood transfusion is the process of transferring blood or blood-based products from one person into the circulatory system of another. ... Bone marrow transplantation or hematopoietic stem cell transplantation (HSCT) is a medical procedure in the field of hematology and oncology that involves transplantation of hematopoietic stem cells (HSC). ...

Contents

Prevalence

Generally, thalassemias are prevalent in populations that evolved in humid climates where malaria was endemic, but affects all races. Thalassemias are particularly associated with Arab-Americans, people of Mediterranean origin, and Asians.[1] The estimated prevalence is 16% in people from Cyprus, 3-14% in Thailand, and 3-8% in populations from India, Pakistan, Bangladesh, and China. There are also prevalences in descendants of people from Latin America, and Mediterranean countries (e.g. Spain, Portugal, Italy, Greece and others). A very low prevalence has been reported from black people in Africa (0.9%), with those in northern Africa having the highest prevalence and northern Europe (0.1%).(4)


Pathophysiology

The thalassemias are classified according to which chain of the hemoglobin molecule is affected (see hemoglobin for a description of the chains). In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected. Structure of hemoglobin. ...


Thalassemia produces a deficiency of α or β globin, unlike sickle-cell disease which produces a specific mutant form of β globin. Sickle-cell disease is a group of genetic disorders caused by sickle hemoglobin (Hgb S or Hb S). ...


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.[2]


Deletion of one of the α loci has a high prevalence in people of African-American or Asian descent, making them more likely to develop α thalassemias. β thalassemias are common in African-Americans, but also in Greeks and Italians.


Alpha (α) thalassemias

The α thalassemias involve the genes HBA1 (Mendelian Inheritance in Man (OMIM) 141800) and HBA2 (Mendelian Inheritance in Man (OMIM) 141850), 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) which have abnormal oxygen dissociation curves. The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ...


There are four genetic loci for α globin, two of which are maternal in origin and two of which are paternal in origin. The severity of the α thalassemias is correlated with the number of affected α globin loci: the greater the number of affected loci, the more severe will be the manifestations of the disease.

  • If one of the four α loci is affected, there is minimal effect. Three α-globin loci are enough to permit normal hemoglobin production, and there is no anemia or hypochromia in these people. They have been called silent carriers.
  • If two of the four α loci are affected, the condition is called alpha thalassemia trait. Two α loci permit nearly normal erythropoiesis, but there is a mild microcytic hypochromic anemia. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron. Alpha thalassemia trait can exist in two forms: one form, associated with Asians, involves cis deletion of two alpha loci on the same chromosome; the other, associated with African-Americans, involves trans deletion of alpha loci on different (homologous) chromosomes.
  • If three loci are affected, the condition is called Hemoglobin H disease. Two unstable hemoglobins are present in the blood: Hemoglobin Barts (tetrameric γ chains) and Hemoglobin H (tetrameric β chains). Both of these unstable hemoglobins have a higher affinity for oxygen than normal hemoglobin, resulting in poor oxygen delivery to tissues. There is a microcytic hypochromic anemia with target cells and Heinz bodies (precipitated HbH) on the peripheral blood smear, as well as splenomegaly. The disease may first be noticed in childhood or in early adult life, when the anemia and splenomegaly are noted.
  • If all four loci are affected, the fetus cannot live once outside the uterus and may not survive gestation: most such infants are dead at birth with hydrops fetalis, and those who are born alive die shortly after birth. They are edematous and have little circulating hemoglobin, and the hemoglobin that is present is all tetrameric γ chains (hemoglobin Barts).[3]

This article discusses the medical condition. ... Erythropoiesis is the process by which red blood cells (erythrocytes) are produced. ... This article discusses the medical condition. ... pale --a loss in color ... This article discusses the medical condition. ... Iron deficiency anemia is the most common type of anemia, and the most common cause of microcytic anemia. ... This article discusses the medical condition. ... pale --a loss in color ... This article discusses the medical condition. ... Target cells, also known as codocytes, which are red blood cells that have the appearance of a target with a bullseye. ... Heinz bodies (also referred to as Heinz-Ehrlich bodies) are inclusions within red blood cells composed of denatured hemoglobin. ... A microscopic view of an abnormal blood film. ... Splenomegaly is an enlargement of the spleen, which usually lies in the left upper quadrant (LUQ) of the human abdomen. ... For other uses, see Fetus (disambiguation). ... Hydrops fetalis is a blood condition in the fetus characterized by an edema in the fetal subcutaneous tissue, sometimes leading to spontaneous abortion. ... Edema (BE: oedema, formerly known as dropsy) is swelling of any organ or tissue due to accumulation of excess fluid. ...

Beta (β) thalassemias

Beta thalassemias are due to mutations in the HBB gene on chromosome 11 (Mendelian Inheritance in Man (OMIM) 141900), 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; 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. The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... “Red cell” redirects here. ...


Any given individual has two β globin alleles.

  • If only one β globin allele bears a mutation, the disease is called β thalassemia minor (or sometimes called β thalassemia trait). This is a mild microcytic anemia. In most cases β thalassemia minor is asymptomatic, and many affected people are unaware of the disorder. Detection usually involves measuring the mean corpuscular volume (size of red blood cells) and noticing a slightly decreased mean volume than normal. The patient will have an increased fraction of Hemoglobin A2 (>2.5%) and a decreased fraction of Hemoglobin A (<97.5%).
  • If both alleles have thalassemia mutations, the disease is called β thalassemia major or Cooley's anemia. This is a severe microcytic, hypochromic anemia. Untreated, this progresses to death before age twenty. Treatment consists of periodic blood transfusion; splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload. Cure is possible by bone marrow transplantation.
  • Thalassemia intermedia is a condition intermediate between the major and minor forms. Affected individuals can often manage a normal life but may need occasional transfusions e.g. at times of illness or pregnancy, depending on the severity of their anemia.

The genetic mutations present in β thalassemias are very diverse, and a number of different mutations can cause reduced or absent β globin synthesis. Two major groups of mutations can be distinguished: This article discusses the medical condition. ... This article discusses the medical condition. ... Blood transfusion is the process of transferring blood or blood-based products from one person into the circulatory system of another. ... Bone marrow transplantation is a medical procedure that involves stem cell transplantation. ...

  • Nondeletion forms: These defects generally involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. Most commonly, mutations occur in the promoter regions preceding the beta-globin genes. Less often, abnormal splice variants are believed to contribute to the disease.
  • Deletion forms: Deletions of different sizes involving the β globin gene produce different syndromes such as (βo) or hereditary persistence of fetal hemoglobin syndromes.

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. A mutation that prevents formation of any delta chains is termed a delta0 mutation, whereas one that decreases but does not eliminate production of delta chain is termed a delta+ mutation. When one inherits two delta0 mutations, no hemoglobin A2 (alpha2,delta2) can be formed. Hematologically, however, this is innocuous because only 2-3% of normal adult hemoglobin is hemoglobin A2. The individual will have normal hematological parameters (erythrocyte count, total hemoglobin, mean corpuscular volume, red cell distribution width). Individuals who inherit only one delta thalassemia mutation gene will have a decreased hemoglobin A2, but also no hematological consequences. The importance of recognizing the existence of delta thalassemia is seen best in cases where it may mask the diagnosis of beta thalassemia trait. In beta thalassemia, there is an increase in hemoglobin A2, typically in the range of 4-6% (normal is 2-3%). However, the co-existence of a delta thalassemia mutation will decrease the value of the hemoglobin A2 into the normal range, thereby obscurring the diagnosis of beta thalassemia trait. This can be important in genetic counseling, because a child who is the product of parents each of whom has beta0 thalassemia trait has a one in four chance of having beta thalassemia major.


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.

Splenomegaly is an enlargement of the spleen, which usually lies in the left upper quadrant (LUQ) of the human abdomen. ...

Treatment and complications

Anyone with thalassemia should consult a properly qualified hematologist. A physician specialising in the treatment of blood diseases. ...


Thalassemias may co-exist with other deficiencies such as folic acid (or folate, a B-complex vitamin) and iron deficiency (only in Thalassemia Minor). Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9. ... Iron deficiency can refer to: Iron deficiency (plant disorder) Iron deficiency (medicine) This is a disambiguation page &#8212; a navigational aid which lists other pages that might otherwise share the same title. ...


Thalassemia Major and Intermedia

Thalassemia Major patients receive frequent blood transfusions that lead to iron overload. Iron chelation treatment is necessary to prevent iron overload damage to the internal organs in patients with Thalassemia Major. Because of recent advances in iron chelation treatments, patients with Thalassemia Major can live long lives if they have access to proper treatment. Popular chelators include deferoxamine and deferiprone. Of the two, deferoxamine is preferred; it is associated with fewer side-effects.[4] Blood transfusion is the taking of blood or blood-based products from one individual and inserting them into the circulatory system of another. ... In medicine, iron overload disorders are diseases caused by the accumulation of iron in the body. ... Chelation therapy is a process involving the use of chelating agents such as EDTA to remove heavy metals from the body. ... Deferoxamine, otherwise known as desferrioxamine or desferal, is a chelating agent used to remove excess iron from the body. ... Please wikify (format) this article as suggested in the Guide to layout and the Manual of Style. ... Adverse effect, in medicine, is an abnormal, harmful, undesired and/or unintended side-effect, although not necessarily unexpected, which is obtained as the result of a therapy or other medical intervention, such as drug/chemotherapy, physical therapy, surgery, medical procedure, use of a medical device, etc. ...


The most common complaint by patients is that it is difficult to comply with the intravenous chelation treatments because they are painful and inconvenient. The oral chelator deferasirox (marketed as Exjade) was recently approved for use in some countries and may offer some hope with compliance. Deferasirox (marketed as Exjade®) is an oral iron chelator. ...


Untreated thalassemia Major eventually leads to death usually by heart failure, therefore birth screening is very important.


In recent years, bone marrow transplant has shown promise with some patients of thalassemia major. Successful transplant can eliminate the patients dependencies in transfusions. An organ transplant is the transplantation of an organ (or part of one) from one body to another, for the purpose of replacing the recipients damaged or failing organ with a working one from the donor. ...


All Thalassemia patients are susceptible to health complications that involve the spleen (which is often enlarged and frequently removed) and gall stones. These complications are mostly prevalent to thalassemia Major and Intermedia patients. The spleen is an organ located in the abdomen, where it functions in the destruction of old red blood cells and holding a reservoir of blood. ...


Thalassemia Intermedia patients vary a lot in their treatment needs depending on the severity of their anemia.


Thalassemia Minor

Contrary to popular belief, Thalassemia Minor patients should not avoid iron-rich foods by default. A serum ferritin test can determine what their iron levels are and guide them to further treatment if necessary. Thalassemia Minor, although not life threatening on its own, can affect quality of life due to the effects of a mild to moderate anemia. Studies have shown that Thalassemia Minor often coexists with other diseases such as asthma[5], and mood disorders[6]. Ferritin is a globular protein found mainly in the liver, which can store about 4500 iron (Fe3+)ions in a hollow protein shell made of 24 subunits. ... This article discusses the medical condition. ... A mood disorder is a condition where the prevailing emotional mood is distorted or inappropriate to the circumstances. ...


Thalassemia prevention and management

Autosomal recessive inheritance

α and β thalassemia are often inherited in an autosomal recessive fashion although this is not always the case. Reports 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. Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... An autosome is a non-sex chromosome. ... It has been suggested that this article or section be merged into Dominance relationship. ... In genetics, the term dominant gene refers to the allele that causes a phenotype that is seen in a heterozygous genotype. ... An autosome is a non-sex chromosome. ... It has been suggested that this article or section be merged into Dominance relationship. ... Genetic counseling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning in order to prevent, avoid or... Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a persons ancestry. ...


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. 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, aggressive birth screening and genetic counseling is recommended.


A screening policy exists on both sides of the island of 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.[7]


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. Malaria is a vector-borne infectious disease caused by protozoan parasites. ... Binomial name Plasmodium vivax Grassi & Feletti 1890 The parasite Plasmodium vivax is the most frequent and widely distributed cause of benign, but recurring (tertian), malaria. ... A merozoite is a daughter cell of protozoan parasites. ... Binomial name Welch, 1897 Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. ... A genetic disorder, or genetic disease is a disease caused, at least in part, by the genes of the person with the disease. ... Sickle-cell disease is a group of genetic disorders caused by sickle hemoglobin (Hgb S or Hb S). ...


Epidemiological evidence from Kenya suggests another reason: protection against severe anemia may be the advantage.[8]. This article discusses the medical condition. ...


People diagnosed with heterozygous (carrier) Beta-Thalassemia have some protection against coronary heart disease.[9] Heterozygote cells are diploid or polyploid and have different alleles at a locus (position) on homologous chromosomes. ... Coronary heart disease (CHD), also called coronary artery disease (CAD), ischaemic heart disease, atherosclerotic heart disease, is the end result of the accumulaation of atheromatous plaques within the walls of the arteries that supply the myocardium (the muscle of the heart) with oxygen and nutrients. ...


Additional facts

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.


Notable patients

Peter “Pete” Sampras (born 12 August 1971), is a former World No. ... Zidane redirects here. ... Bachchan redirects here. ... John Norman Maguire (born September 15, 1956, Murwillumbah, New South Wales) is a former Australian cricketer who played in 3 Tests and 23 ODIs from 1983 to 1984. ...

References

  1. ^ E. Goljan, Pathology, 2nd ed. Mosby Elsevier, Rapid Review Series.
  2. ^ Kumar et al, eds. Robbins and Cotran's Pathologic Basis of Disease, 7th ed.
  3. ^ E. Goljan, Pathology, 2nd ed. Mosby Elsevier, Rapid Review series.
  4. ^ Maggio A, D'Amico G, et al. (2002). "Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial". Blood Cells Mol Dis 28 (2): 196–208. PMID 12064916. 
  5. ^ Palma-Carlos AG, Palma-Carlos ML, Costa AC (2005). ""Minor" hemoglobinopathies: a risk factor for asthma". Allerg Immunol (Paris) 37 (5): 177–82. 
  6. ^ Brodie BB (2005). "Heterozygous β-thalassaemia as a susceptibility factor in mood disorders: excessive prevalence in bipolar patients". Clin Pract Epidemiol Mental Health 1: 6. doi:10.1186/1745-0179-1-6. 
  7. ^ Leung NT, Lau TK, Chung TKH (2005). "Thalassemia screening in pregnancy". Curr Opinion in Ob Gyn 17: 129–34. 
  8. ^ Wambua S, Mwangi TW, Kortok M, Uyoga SM, Macharia AW, Mwacharo JK, Weatherall DJ, Snow RW, Marsh K, Williams TN (2006). "The effect of α+-Thalassaemia on the Incidence of Malaria and other diseases in children living on the coast of Kenya". PLoS Med 3(5): e158.. 
  9. ^ Tassiopoulos S,Deftereos S,Konstantopoulos K,Farmakis D,Tsironi M,Kyriakidis M,Aessopos A. (2005). "Does heterozygous beta-thalassemia confer a protection against coronary artery disease?". Ann N Y Acad Sci. 1053: 467–70. 

A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ...

External links


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