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Thalassemias

Page history last edited by Tjker 14 years, 5 months ago

 

Thalassemias

 

 

Introduction

 

Thalassemia is an inherited condition passed on from parents to their offspring via the genes; it is a recessive condition which correlates to the improper structure of globin chains in the blood (Mcann et al).

 

 

 

 

 

 

 

                                    Fig: 1

                                    Pattern of inheritance 

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There are three types of thalassemias. Beta, alpha and delta. The thalassemias are prevalent worldwide and is characterised by the presence or absence of the making of one or many of the globin chains. The type of thalassemia observed is dependent on which globin chain i.e.: beta gamma or delta chain is made; mainly the alpha thalassemias are common in populations in Africa, Asia and the Mediterranean, while beta thalassemia mainly occurs only in Asia and the Mediterranean. (Luz et al.2006). Symptoms of thalassemia include impaired growth of the individual as well as endocrine disorders such as hypogonadism. This is due to chronic anaemia also iron overload in the blood, which is marginally accounts for mortality and morbidity. Excess iron is mainly deposited in the visceral organs leading to tissue damage which then causes dysfunction of the organs which cause failure. (Rund et al.2005) 

 

 

 

Beta thalassemia

 

This type of thalassemia is mainly caused by point mutations rather than deletions. People with beta thalassemia require blood transfusions and iron chelation therapy to manage the condition, or bone marrow transplant would be required to ameliorate the condition. (Ning Su et al.2003). As one of the processes that occur to the blood is oxidative damage to the erythrocytes, which is prevented by an alpha haemoglobin protein which stabilises the alpha chains hence, preventing damage. two processes, haemolysis and ineffective erythropoiesis is known to cause anaemia in thalassemia. apoptosis at an accelerated rate is known to be the cause of ineffective erythropoisis, which is due to an extra alpha chain in the erythoid precursors, in contrast during normal erythropoiesis apoptosis are regulators and is required for the maturation of erythoids. a peptide hormone called hepicidin inhibits iron absorption in the small bowel, this peptide increases in relation to ambient iron levels when elevated. this peptide is low in patients that have thalassemia which contribute to iron overload. iron chelation therapy enables the life expectancy of thalassemia sufferers to double.

 

some of the treatments for beta thalasemmia include gene therapy, mainly against the disease from beta globin gene, which involves insertion of the normal type of the gene into stem cells, however development of a vector is a constraint, as the therapeutic allele would have to be expressed over a long period of time. other precautionary measures included PCR (polymerase chain reaction) to detect if any point mutations or deletions are present in chronic villus samples of pregnant women to start first trimester testing of thalassemia. PCR is then required to look for mutations from cells that have been removed. (Rund et al.2005)

 

other technologies used to detect thalassemia are Denaturing high performance liquid chromatography (DHPLC). this enables single base substitutions, insertions or deletions to be detected. DHPLC enabled common and rare mutations to be detected, which indicated there is a correlation between discreptancies with arrangements with polymorphisms of restriction fragment lengths or haplotypes of beta globin cluster (Ning su et al.2003)

 

 

Alpha thalassemia 

 

Alpha thalassemia is observed by when hypochromic anaemia is present, when there’s a reduced number of alpha globin chains in adult haemoglobin. there are more than fifty mutations of the alpha cluster have been observed. these deletions have caused either one or both of the haplotypes to be removed. point mutations are seldom been observed in the sequences i.e.: initial codons, splice sites and translational codons. studies have also shown that people who have a condition known as mydeloplasia who have thalassemia have found somatic mutations in globin gene expression called ATRX(alpha thalassemia mental retardation x linked). mutations of ATRX can be responsible for premature or inappropriate silencing of alpha globin expression during the process of terminal erythropoiesis when the action of transcription is usually the greatest. in the process of terminal differentiation ATRX exerts its effects on erythroid cells.  the method of how ATRX mutations affect and downregulate alpha globin expression is still unknown. This is a rare condition with around 100 families affected to date. it is responsible for the cause of DNA methylation. (Steensma et al.2005)

 

Initially the ATRX gene was found in mice and then humans. by the use of using a positional candidate gene approach it was shown to be responsible for disease. the composition of the gene includes 35 exons and it spans greater than 300 kilo bases of the genomic DNA. The protein for ATRX is a nuclear protein which is usually linked to the short arm of areocentric chromosomes during the process of mitosis 5 and closely associated with the nuclear matrix during the process of interphase, these processes are due differences in the cell cycle because of the action of phosphorylation. the human version of the ATRX protein is thought to closely resemble another protein which is part of the chromatin in yeast (EZH2). ATRX is also thought to play a role in the remodelling of chromatin, activation or repression of targeted loci through a process which is dependent on methylation.

 

Syndrome X-linked mental retardation syndrome which is related to alpha thalassemia. Symptoms include severe mental retardation, absent speech or speech reduced to a few words, delayed developmental milestones and congenital microcephaly. The patient’s facial structure is affected; such are carp-shaped mouth, and inverted nostrils, midface hypoplasia, telecanthus and epicanthic folds. found, ranging from cryptorchidism and hypospadia to ambiguous external genitalia. (Villard et al.2002)

it is thought that by having alpha thalassemia, the mechanism of action of the ATRX gene would lead to the suffers displaying these conditions.

 

Delta thalassemia

delta thalassemia is caused by the decrease in or the absence of the synthesis of the delta globin chain; define d as delta thalessemia positive or negative. Delta thalasseimia is also looked at when testing for beta thalassemia, if the heterozygous inheritance of delta negative thalassemia and beta thalassemia results in expression of beta thalassemia at a normal level of haemoglobin.

Few mutations were discovered to be responsible for delta thalasemia; these mutations caused abnormal splicing, frame shift mutations and mutations causing amino acid substitution.

. Erythroid specific transcription factor binding activity of GATA-1 was elevated, which suggests that this is the mutation responsible for malfunction of the delta globin gene. Interference with the motif that binds GATA -1 stops globin gene expression of delta thalassemia.

Base substitution of T-C is known to effect delta globin gene expression in an adverse manner. (Matsudo et al.1992)

The delta globin gene encodes the delta globin chain of haemoglobin. The delta globin genes is located on chromosome 11 within the beta like globin gene cluster, at a position that is +69 spaces from the addition site of the globin gene a nucleotide substitution occurs, which has indicated that  is responsible for the malfunction  of the delta globin gene. This mutation has bee noted to affect RNA formation at the 3 prime ends. Increasing activity of the delta globin gene that has a base substitution of cytosine in place of thymine seems to have been the cause of GATA-1 protein, which has been a regulator of delta and beta globin expression. Motifs of the GATA also may have a negative effect on beta like but not delta like expression. The studies of the delta + 69 mutation is vital to ascertain whether this mutation is what causes the defective  function of the delta globin gene and what aspect does the GATA have on the 3’ when regulating delta globin gene expression.(Moi et al.1992)

 

Molecular biology of Thalassemias

 

To date, more than 1000 inherited mutations that affect either the structure or synthesis of the α- and β-globin chains are known. Mutations that result in β or α thalassemia are similar in principle but different in their patterns. Presently, more than 200 molecular defects known to down regulate the expression of β globin have been characterized. Such defects result in various types of β thalassemia.

Major deletions in β thalassemia are unusual, and most of the encountered mutations are single base changes, small deletions, or insertions of 1-2 bases at a critical site along the gene

The fused δ/β gene is under the control of a δ-globin gene promoter region (the β gene promoter is deleted in the process). Because the δ gene promoter carries mutations that lead to ineffective transcription, the fused δ/β chains are produced in limited amounts, resulting in thalassemia. This is in addition to the hemoglobinopathy.

Conversely, in d/β-0 thalassemia, a large deletion occurs in the β-globin gene cluster, removing both the δ and the β genes, which can also extend to involve all globin genes on chromosome 11, thus producing ε, γ, δ, and β-0 thalassemia.

 

Today there are various mutations that are inherited that affect the making of the alpha and beat chains. It is known that there are two hundred defects that effect the expression of the beta globin gene which cause various types of beta thalassemia. Also in delta thalassemia there is a deletion in the beta globin cluster deleting the alpha and beta genes which extend to the genes on chromosome 11.

What happens in al forms of thalassemia is imbalanced globin chain synthesis. The chains in excess in alpha thalassemia are delta in early life and beta later on in life, these chains form homotetramers make haemoglobin chains which could be delta of beta, and these are responsible for the different manifestations of thalassemia.

Alpha chains that accumulate in the red blood cell precursors are insoluble, precipitate in the cell, interact with the membrane, and disrupt cell division. This leads to excessive intramedullary destruction of the red blood cells.

The ability of some re blood cells to maintain the production of γ chains, which are capable of pairing with some of the excessive α chain to produce Hb F, is advantageous. Binding some of the excess a chains undoubtedly reduces the symptoms of the disease and provides additional Hb with oxygen-carrying ability. The action of the red blood cells to maintain the production of delta chains which pairs up with excess alpha chains to produce haemoglobin f is an advantage

increased production of Hb F, in response to severe anaemia, creates a mechanism to protect the RBCs in persons with β thalassemia. The elevated Hb F level increases oxygen affinity, leading to hypoxia, which, together with the profound anaemia, stimulates the production of erythropoietin. Therefore, severe expansion of the ineffective erythroid mass leads to severe bone expansion and deformities. Both iron absorption and metabolic rate increase, adding more symptoms to the clinical and laboratory manifestations of the disease.

If the chronic anaemia in these people with the condition is corrected with regular blood transfusions, the severe expansion of the ineffective marrow is reversed. Adding a second source of iron would theoretically result in more harm to the patient. However, this is not the case because iron absorption is regulated by 2 major factors: ineffective erythropoiesis and iron status in the patient.

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By administering blood transfusions, the ineffective erythropoiesis is reversed, and the hepcidin level is increased; thus, iron absorption is decreased and macrophages retain iron.

Iron status is another important factor that influences iron absorption. In patients with iron overload, the iron absorption decreases because of an increased hepcidin level.  this is not what happens in patients with severe β thalassemia because a putative plasma factor overrides such mechanisms and prevents the production of hepcidin. Therefore, iron absorption continues despite the iron overload status.

The effect of hepcidin on iron recycling is carried through another hormone called ferroportin, which exports iron from enterocytes and macrophages to the plasma and exports iron from the placenta to the foetus. Ferroportin is up regulated by iron stores and down regulated by hepcidin. This could possibly explain why patients with β thalassemia who have similar iron loads have different ferritin levels based on whether or not they receive regular blood transfusions. http://emedicine.medscape.com/article/958850-overview

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Fig: 2

Structure of the gene for thalassemia

 

 

 

 

 

Treatments

 The only cure for thalassemia is to use stem cell transplantation to correct the genetic cause of thalassemia. One of the requirements for this procedure is that the donor and the recipient be compatible with one another otherwise immunosuppressant drugs have to be given so acceptance of the cells can occur. The differences in blood groups would not have an affect as the plasma or rd blood cells are removed before the cells are inserted.  When the recipient’s bone marrow is infused they then receive a combination of anti viral anti fungal and anti bacterial drugs.  Blood tests are also carried out to determine whether any adverse reactions take place.

 Although this process changes helps with the bone marrow, people are still required to undergo iron removal to reduce the risk of mortality from this condition. (Lucarelli et al.2002) Iron chelation is also used; Deferoxamine compound used which does not enter cells which is administered parenternally causing chelated iron to be excreted in the urine and the stool. It was also found to be some less effective against cardiac iron overloading and heart failure. (Schrier and Angelucci.2005)

 

 

 

                                                                                                                    

 

 

 

 

References

 

1. Yi-Ning Su, Chien-Nan Lee,2 Chia-Cheng Hung, Chi-An Chen,2 Wen-Fang Cheng,2 Po-Nien Tsao, Chia-Li Yu,1 and Fon-Jou Hsieh, 2003, Rapid Detection of b-Globin Gene (HBB) Mutations Coupling Heteroduplex and Primer-Extension

Analysis by DHPLC, HUMAN MUTATION 22:326^336, viewed 3 September 2009.

 

2. Deborah Rund, M.D., and Eliezer Rachmilewitz, M.D, 2005, b -Thalassemia, the New England journal of medicine, viewed 3 September 2009.

 

3. Julio A. da Luz1, Mónica Sans, Elza Miyuki Kimur, Dulcinéia Martins Albuquerque4,

Maria de Fatima Sonati and Fernando Ferreira Costa, 2006, -thalassemia, HbS, and -globin gene cluster haplotypes in two

Afro-Uruguayan sub-populations from northern and southern Uruguay, Genetics and Molecular Biology, 29, 4, 595-600, accessed 2 September 2009

 

4. David P. Steensma, Richard J. Gibbons and Douglas R. Higgs,

Acquired {alpha}-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies, 2005 105: 443-452, accessed 2 September 2009

5. M Matsuda, N Sakamoto and Y Fukumaki, 1992

Delta-thalassemia caused by disruption of the site for an erythroid promoter specific transcription factor, GATA-1, in the delta-globin gene, 1347-1351, accessed 2 September 2009

 

6. P tu Moi, G Loudianos, J Lavinha, S Murru, P Cossu, R Casu, L Oggiano, M Longinotti, A Cao, 1992,  Delta-thalassemia due to a mutation in an erythroid-specific binding protein sequence 3' to the delta-globin gene, accessed 2 September 2009

 

7. Laurent Villard*,1 and Michel Fontes, 2002, Alpha-thalassemia/mental retardation syndrome,

X-Linked (ATR-X, MIM #301040, ATR-X/XNP/XH2 gene

MIM #300032), European Journal of Human Genetics (2002) 10, 223 ± 225, accessed 2 September 2009

 

8. <http://community.blackdoctor.org/ViewBlogPost.aspx?BPID=264 > Accessed % October 2009, 8:23 pm

 

9. <http://emedicine.medscape.com/article/958850-overview> Accessed 8 October, 8:15 pm

 

10. Lucarelli G, Andreani M,  Angelucci E, 2002, the cure of thalassemia by bone marrow transplantation, Elesvier service, blood reviews 16, 81-85

 

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