Thalassemia: Wikis

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Thalassemia
Classification and external resources
ICD-10 D56.
ICD-9 282.4
MedlinePlus 000587
eMedicine ped/2229 radio/686
MeSH D013789

Thalassaemia (American spelling, "thalassemia") 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 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.[1] 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 people from the middle east and North Africa. 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.

The thalassemia trait may confer a degree of protection against malaria, which is or was prevalent in the regions where the trait is common, thus conferring a selective survival advantage on carriers, and perpetuating the mutation. In that respect the various thalassemias resemble another genetic disorder affecting hemoglobin, sickle-cell disease.

Contents

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.[2] 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%[3] 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 also suffered from thalassemia, with as many as 40%[citation needed] of studied pre-dynastic and dynastic mummies found to carry 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 Nile Delta, Red Sea Hill Region and especially amongst the Siwans.

Pathophysiology

Normal haemoglobin is composed of two chains each of α and β globin. Thalassemia patients produce a deficiency of either α or β globin, unlike sickle-cell disease which produces a specific mutant form of β globin.

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.

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.

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Alpha (α) thalassemias

The α thalassemias involve the genes HBA1[4] and HBA2,[5] 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 ,[6] also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as (βo or β thalassemia major) if they prevent any formation of β chains (which is the most severe form of beta Thalassemia); they are characterized as (β+ or β thalassemia intermedia) 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.

Genetic prevalence

Thalassemia has an autosomal recessive pattern of inheritance

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.

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.[7]

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.[8]
  • 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 thalassemia trait) they are referred to the local designated health post for genetic counseling.[9]

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.[10] In 2009, a group of doctors and specialists in Chennai and Coimbatore registered the successful treatment of thalassemia in a child using a sibling's umbilical cord blood.[11]

Benefits

Being a carrier of the disease may confer a degree of protection against malaria, as it is quite common among people of 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's red blood cell (RBC) environment unsuitable for the merozoites of the more 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.[12]

People diagnosed with heterozygous (carrier) β thalassemia have some protection against coronary heart disease.[13]

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.[citation needed]

References

  1. ^ Hemoglobinopathies and Thalassemias
  2. ^ E. Goljan, Pathology, 2nd ed. Mosby Elsevier, Rapid Review Series.
  3. ^ http://www.dmsc.moph.go.th/webrOOt/ri/Npublic/p04.htm
  4. ^ Online 'Mendelian Inheritance in Man' (OMIM) 141800
  5. ^ Online 'Mendelian Inheritance in Man' (OMIM) 141850
  6. ^ Online 'Mendelian Inheritance in Man' (OMIM) 141900
  7. ^ Tesoriere L, Allegra M, Butera D, Gentile C, Livrea MA (July 2006). "Cytoprotective effects of the antioxidant phytochemical indicaxanthin in beta-thalassemia red blood cells". Free Radical Research 40 (7): 753–61. doi:10.1080/10715760600554228. PMID 16984002. 
  8. ^ Leung TN, Lau TK, Chung TKh (April 2005). "Thalassaemia screening in pregnancy". Current Opinion in Obstetrics & Gynecology 17 (2): 129–34. doi:10.1097/01.gco.0000162180.22984.a3. PMID 15758603. 
  9. ^ Samavat A, Modell B (November 2004). "Iranian national thalassaemia screening programme". BMJ (Clinical Research Ed.) 329 (7475): 1134–7. doi:10.1136/bmj.329.7475.1134. PMID 15539666. 
  10. ^ Spanish Baby Engineered To Cure Brother
  11. ^ His sister's keeper: Brother's blood is boon of life, Times of India, 17 September 2009
  12. ^ Wambua S, Mwangi TW, Kortok M, et al. (May 2006). "The effect of alpha+-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya". PLoS Medicine 3 (5): e158. doi:10.1371/journal.pmed.0030158. PMID 16605300. 
  13. ^ Tassiopoulos S, Deftereos S, Konstantopoulos K, et al. (2005). "Does heterozygous beta-thalassemia confer a protection against coronary artery disease?". Annals of the New York Academy of Sciences 1054: 467–70. doi:10.1196/annals.1345.068. PMID 16339699. 

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