Hemoglobinopathies Bara’a Bayan Eiad Ahlam Ahmad

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. 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.

α-globin-like genes on chromosome 16 β-globin-like genes on chromosome 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). α-globin-like genes on chromosome 16 β-globin-like genes on chromosome 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). Organization of the globin genes

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) 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)

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. 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.

Destribution of hemoglobinopathies

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. 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.

RBC in sickle cell disease normal RBC

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

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.

Sickling causes tissue anoxia The substitution of the nonpolar valine 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 The substitution of the nonpolar valine 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 → → → →

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 O 2 tension Increased CO 2 concentration Decreased pH Increased concentration of 2,3-BPG in RBC 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 O 2 tension Increased CO 2 concentration Decreased pH Increased concentration of 2,3-BPG in RBC

Possible selective advantage of heterozygous state Heterozygotes for the sickle-cell gene are less susceptible to malaria caused by the parasit Plasmodium 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.

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

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

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 Hb C 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 Hb C disease.

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

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

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

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 ( α 2 β 2) becomes → ( α 2 β s2 ) Glu a.a → Val a.a It occurs in individuals who have inherited two mutant genes that codes for synthesis of the β chains of globin molecule So ( α 2 β 2) becomes → ( α 2 β s2 ) Glu a.a → Val a.a

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

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

Thalassemia Thalassemia: (Thalassic/ emia) In thalassemia the synthesis of α or β chains are defective It can be caused either by deletional or point mutation Thalassemia: (Thalassic/ emia) In thalassemia the synthesis of α or β chains are defective It can be caused either by deletional or point mutation

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

All hemoglobinopathies follow recessive form of inheritance Example : thalassemia

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

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(β 4 ) disease → severe If all 4 are defective → Hb Bart (γ 4 ) disease → fetal death 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(β 4 ) disease → severe If all 4 are defective → Hb Bart (γ 4 ) disease → fetal death

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 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

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 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

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

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. 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.

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. 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.

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. 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.

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. 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.