Hemoglobinopathies

1. Hemoglobinopathies

2. Hemoglobinopathies • defined as a family of disorders caused either by: 1- production of abnormal hemoglobin molecule such as: HbS & HbC 2- Synthesis of insufficient quantities of normal hemoglobin such as: thalassemias 3- rarely, both.

3. Organization of the globin genes • α-globin-like genes on chromosome 16 • β-globin-like genes on chromosome 11 1- α-Gene family: contains a- two genes for the α-globin chains b-The ζ-gene which is expressed. c- other globin-like genes that are not expressed (pseudogenes).

4. 2- β-gene family: contains a- single gene for the β-globin chain b- four other β -globin-like genes • the ε-gene (like ζ-gene) • two Ɣ-genes (HbF) • δ-gene (HbA2)

5. Globin Chain Synthesis • expression begins in nucleus • the gene is transcribed → mRNA precursor • two introns must be removed • splicing → linear manner of exons • processing → mature mRNA • translating by ribosomes in cytosol • producing globin.

7. Destribution of hemoglobinopathies

8. Sickle-cell anemia(hemoglobin S disease) The most common disorder resulting from the production of a variant hemoglobin. It is a homozygous recessive disorder occurring in individuals who have inherited two mutant genes that code for synthesis of the ß-chains of the globin molecules.

9. RBC in sickle cell disease normal RBC

10. Sickle-cell anemia is characterized by a lifelong hemolytic anemia, painful crises, and increased susceptibility to infections and other indications of poor circulation.

11. Amino acid substitution in HbS ß-chains A molecule of HbS contains two normal α-globin chains & two mutant ß-globin chains in which glutamate at position six has been replaced with valine. Therefore, during electrophoresis at alkaline pH, HbS migrates more slowly toward the anode than does HbA.

13. Sickling causes tissue anoxia The substitution of the nonpolarvaline for a charged glutamate decrease in the solubility of HbS molecules aggregate to form fibers deform the RBC into a crescent or sickle shape → frequently block the flow of blood in the small capillaries localized anoxia → causes pain and eventually daith of cells in the vicinity → → → →

14. Variables that increase sickling The extent of sickling and the severity of disease is increased by variables that increase the proportion of HbS in the deoxy state such as : Decreased O2 tension Increased CO2 concentration Decreased pH Increased concentration of 2,3-BPG in RBC

15. Possible selective advantage of heterozygous state Heterozygotes for the sickle-cell gene are less susceptible to malaria caused by the parasitPlasmodium falciparum. Because it spends an obligatory part of its life cycle in the RBC and these cells in individuals heterozygous for HbS, as well as in homozygotes, have a shorter life span, the parasite can’t complete this stage for development.

16. Hemoglobin C disease Glutamate Lysine In the 6th position of β-globin chain

17. Symptoms • Mild but chronic hemolytic anemia • Do NOT suffer from infarctive anemia • No specific therapy is required

18. Hemoglobin SC disease • Type of the red cell sickling diseases • Some β-globin chain have the sickle cell mutation While the other β-globin chains carry the mutation found in HbC disease .

19. The patient is heterozygous Both of β-globin chains are abnormal • Hemoglobin levels , even higher or lower than normal range

20. Symptoms • Less frequent and less severe painful crises than sickle cell anemia

22. hemoglobinopathies quantitative qualitative Thalassemia (Hb quantity less than normal) AbonrmalHb Cause : point or deletional mutaion Cause : point mutation ( single nucleotide alteration) HbS βthalassemia α thalassemia HbC HbSC

23. Sickle cell anemia (HbS) It occurs in individuals who have inherited two mutant genes that codes for synthesis of the β chains of globin molecule So (α2β2) becomes → (α2βs2 ) Glua.a→ Val a.a

24. HbC Glua.a → Lys a.a HbSC Some of chain have the (HbS) and some have (HbC) mutation RBC in sickle cell disease normal RBC

25. Normal hemoglobin structure Structure: 4 polypeptide subunit Type: 1. Hb A → 2α / 2β 2. Hb A2 → 2α / 2δ 3. Hb F → 2α / 2γ Function: transport of O2 from (lungs → tissue)

26. Thalassemia • Thalassemia: (Thalassic/ emia) • In thalassemia the synthesis of αorβchains are defective • It can be caused either by deletional or point mutation

27. Thalassemia No globin chain is produced Synthesized in reduced level β˚ orα˚ thalassemia β+or α+ thalassemia

28. All hemoglobinopathies follow recessive form of inheritance Example : thalassemia

29. Thalassemias βThalassemia : synthesis of β chains is decreased or absent cause: point mutation α Thalassemia : synthesis of α chains is decreased or absent cause: deletional mutation

30. 4 genes code for α chains • If one is defective → individual is called silent carrier of α thalassemia→ no symptoms • If two are defective → α thalassemia trait • If three are defective →Hb H(β4) disease → severe • If all 4 are defective →Hb Bart (γ4) disease → fetal death

31. β-thalassemia • synthesis of β-globin chains is decreased or absent • α-globin precipitate causing premature death of cells initially destined to become mature red blood cells • two copies of β-globin gene • Levels:- • 1- β-thalassemia trait (β-thalassemia minor) • 2- β-thalassemia major

33. physical manifestations appear only after birth. why? • Infants born with β-thalassemia major seem healthy at birth then become severly anemic during first or second year of life. • They require regular transfusion of food. • iron overload (hemosiderosis syndrome) • Causes death between ages of 15 and 25 years

34. β-thalassemia may be inherited with other abnormal hemoglobins. • Sickle-βthalassemia • E-beta thalassemia • People should receive regular medical care

35. How do people find out that they carry beta thalassaemia? By having a special blood test “for haemoglobin disorders”. This usually involves two steps: .The first step is to measure the size of their red blood cells. .The second step is to analyse the types of haemoglobin in their blood.

36. Are they weak people? Carriers of beta thalassaemia are not ill, and are no more likely to get ill than other people. Carrying beta thalassaemia does not make them weak, and they can do any kind of work they choose.

37. Is there any treatment to get rid of beta thalassaemia? No, a person who is born carrying beta thalassaemia will always carry it. • Can carrying beta thalassaemia turn into a serious form of thalassaemia? It cannot.

38. Can a carrier of beta thalassaemia be a blood donor? They can give blood like other people, provided they are not anaemic. • Is it a bad thing to carry beta thalassaemia? It is not. Carriers of beta thalassaemia are healthier than other people in several ways. For example, they have some natural protection against severe forms of malaria.

39. Best Wishes The End