thalassemia

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Abdullah ali alqarni Student of medicine Imam university Dr.abdullah22@hotmail.com abdullah ali alqarni

What is thalassemia?:

Thalassemia is a group of inherited disorders of hemoglobin synthesis characterized by a reduced or absent output of one or more of the globin chains of adult hemoglobin . The name is derived from the Greek words Thalasso = Sea" and " Hemia = Blood" in reference to anemia of the sea . Reduction of α or β chain synthesis causes α or β- thalassaemia respectively. What is thalassemia? abdullah ali alqarni

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There are many variations at the gene level but the picture of hypochromasia and microcytosis is universal. The degree of chain imbalance determines the clinical picture from severe anaemia to a clinically silent form. Thalassaemia may involve other globin chains but the α and β chains are clinically of greater importance. abdullah ali alqarni

Hemoglobin Review:

Each complex consists of : Four polypeptide chains, non-covalently bound Four heme complexes with iron bound Four O2 binding sites Hemoglobin Review abdullah ali alqarni

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Globin Chains:

Alpha Globin 141 amino acids Coded for on Chromosome 16 Found in normal adult hemoglobin, A1 and A2 Beta Globin 146 amino acids Coded for on Chromosome 11, found in Hb A1 Delta Globin Found in Hemoglobin A2--small amounts in all adults Gamma Globin Found in Fetal Hemoglobin Zeta Globin Found in embryonic hemoglobin Globin Chains abdullah ali alqarni

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Normal HumanHaemoglobins:

Normal HumanHaemoglobins Haemoglobin Structural formula Adult Hb-A  2  2 97% Hb-A 2  2  2 1.5-3.2% Fetal Hb-F  2  2 0.5-1% Hb-Bart’s  4 Embryonic Hb-Gower 1  2  2 Hb-Gower 2  2  2 Hb-Portland  2  2 abdullah ali alqarni

The common abnormal haemoglobins:

The common abnormal haemoglobins Haemoglobin Structural formula Hb-S  2  2 6 glu  val Hb-C  2  2 6 glu  lys Hb-E  2  2 26 glu  lys Hb-D Punjab  2  2 121 glu  gln abdullah ali alqarni

Genetics:

Alpha globins are coded on chromosome 16 Two genes on each chromosome Four genes in each diploid cell Gene deletions result in Alpha- Thalassemias Also on chromosome 16 are Zeta globin genes—Gower’s hemoglobin (embryonic) Beta globins are coded on chromosome 11 One gene on each chromosome Two genes in each diploid cell Point mutations result in Beta- Thalassemias Also on chromosome 11 are Delta ( Hb A2) and Gamma ( Hb F) and Epsilon (Embryonic) Genetics abdullah ali alqarni

Chromosomes:

Chromosomes Source: Thalassemia.com abdullah ali alqarni

Types of Thalassemia:

There are two basic groups of thalassaemia .  thalassemia: There are four types categorized according to the severity of their effects on persons with thalassemia. ß thalassemia: There are 3 types categorized according to severity: Thalassemia minor Thalassemia intermedia Thalassemia major Types of Thalassemia abdullah ali alqarni

α -Thalassemia:

α -Thalassemia An absence or deficiency of α -chain synthesis due to delation of α -genes. abdullah ali alqarni

Pathogenesis of α-Thalassaemia:

Pathogenesis of α - Thalassaemia In normal individual HbA , HbA2 and HbF need α -chain for their formation. 4 genes of α -chain, each pair on short arm of chromosome 16 present with genotype α , α / α , α . In α - thalassaemia , delation of α -genes  reduction or absence of synthesis of α -chain depending on number of α -gene delation . abdullah ali alqarni

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↓ α -chain synthesis free γ -chain in the fetus & β -chain in infant of 6 months, and continue in the rest of life . Complementary 4 γ and 4 β are aggregated  Hb Bart ( 4 γ ) and HbH (4 β ), respectively. abdullah ali alqarni

Variants of α-Thalassaemia:

Variants of α - Thalassaemia Silent carrier Delation of single α -gene Genotype α / αα Asymptomatic Absence of RBC abnormality Thalasaemia trait Delation of 2 α -genes Genotype --/ αα Asymptometic , minimal or no anaemia Minimal RBC abnormalities abdullah ali alqarni

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Hb H disease Delation of 3 α -genes Genotype --/- α 75% reduction of α -chain 25% α -chain synthesis  small amount of HbF , HbA , & HbA 2 Fetus can survive Severe anaemia Severe RBC abnormalites Hydrops fetalis Delation of all α -genes Genotype --/-- Absence of α -chain synthsis Only Hb Bart ( γ 4 ) is produced (High affinity for O 2 and can not dissociate O 2 to tissue) abdullah ali alqarni

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β-Thalassaemia:

β - Thalassaemia An absence or deficiency of β -chain synthesis of adult HbA β Chain synthesis Hb-A γ and δ chain Hb-A = α 2 β 2 abdullah ali alqarni

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β - thalassaemia major Mutation of normal β -gene  β 0 -gene  absence HbA  increased HA 2 and HbF genotype – β 0 β 0 β - thalassaemia intermedia ↑ HbA 2 ↑ HbF ↓ HbA Genotype β + β + or β 0 β β - thalassaemia minor ↑HbA 2 HbA normal HbF normal abdullah ali alqarni

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On the basis of synthetic ability β -genes are designated as β gene – can synthesize normal amount of β -chain β + gene – can synthesize reduced amount of β -chain β 0 gene – cannot synthesize β -chain abdullah ali alqarni

Pathophysiology of β-Thalassaemia:

Pathophysiology of β - Thalassaemia Various mutation in β -gene Complete or partial absence of β -chain Decreased adult HbA α -chain synthesis remain normal Free complementary α -chain – unstable and precipitate within normoblasts as insoluble inclusions Cell membrane damage & impaired DNA synthesis apoptosis i.e. ineffective erythropoeisis abdullah ali alqarni

70-80% marrow normoblasts undergo apoptosis:

70-80% marrow normoblasts undergo apoptosis Inclusion bearing red cells undergo sequestration & destruction in spleen abdullah ali alqarni

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Transmission of ß thalassemia If a carrier ( thalassemia minor ) marries a non-carrier, on average half of their children will be carriers, but none will develop thalassemia major. abdullah ali alqarni

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Transmission ß of thalassemia - Cont However if two carriers marry, in each pregnancy there is a 25% chance of a non-carrier child, a 50% chance of a carrier child (thalassemia minor), and a 25% chance of a child with thalassemia major. abdullah ali alqarni

An example of inheritance: a carrier married to a normal person:

An example of inheritance: a carrier married to a normal person Source: Emirates Thalassemia Society abdullah ali alqarni

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An example of inheritance- Cont: marriage between two carriers:

An example of inheritance - Cont : marriage between two carriers Source: Emirates Thalassemia Society abdullah ali alqarni

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Types of ß thalassemia:

Thalassemia Minor ( Trait) . This can also be called (carrier state), meaning that the person carries the genetic trait for thalassemia. Such people usually practice normal life, but may suffer from a mild form of anemia. Types of ß thalassemia abdullah ali alqarni

Types of ß thalassemia- Cont:

Thalassemia Intermedia . Caused by the reduced availability of beta chains in hemoglobin and can lead to moderate to severe anemia and an array of complications including bone deformities and splenomegaly. Types of ß thalassemia- Cont abdullah ali alqarni

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Types of ß thalassemia- Cont:

Thalassemia Major ( Cooley's Anemia) . Caused by the unavailability of beta chains in hemoglobin leading to a very severe and fatal if left untreated anemia. It requires regular blood transfusions leading to iron-overload which is treated with chelation therapy to prevent death from organ failure. Types of ß thalassemia- Cont abdullah ali alqarni

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Signs & Symptoms:

Thalassaemia Minor : Usually no signs or symptoms except for a mild anemia. Thalassaemia Major : 1. Paleness, Jaundice or yellow coloured skin. 2. Growth retardation. 3. Bony abnormalities specially of the facial bones. 4. Enlarged spleen and liver. Signs & Symptoms abdullah ali alqarni

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Laboratory diagnosis :

Thalassemia minor: -Blood smear shows hypochromia and microcytosis (similar to Iron Deficiency Anemia). -Blood indices: MCV< 75 fl , Hb usually> 10, Hematocrit> 30%, RDW < 14%. -Hemoglobin A2 often elevated > 3%, sometimes reaching 7-8%. Laboratory diagnosis abdullah ali alqarni

Laboratory diagnosis- Cont:

Thalassemia major: -Blood smear shows profound microcytic anemia, with extreme hypochromia , tear drop, target cells and nucleated RBCs. -Hemoglobin may be very low at 3-4 g/dl. Laboratory diagnosis- Cont abdullah ali alqarni

Blood picture of a ß thalassemia major patient :

Blood picture of a ß thalassemia major patient Source: Cooley’s Anemia Foundation abdullah ali alqarni

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Adult Reference Ranges for Red Blood Cells:

Women Men Units 12.0-15.0 13.6-17.2 g/ dL Hemoglobin ( Hb ) 33-43 39-49 % Hematocrit (HCT) 3.5-5.0 4.3-5.9 ×10 6 /mm 3 Red cell count 0.5-1.5 0.5-1.5 % Reticulocyte count 76-100 76-100 fL Mean cell volume (MCV) 27-33 27-33 pg Mean cell Hb (MCH) 33-37 33-37 g/ dL Mean cell Hb concentration (MCHC) 11.5-14.5 Red cell distribution width (RDW) Adult Reference Ranges for Red Blood Cells abdullah ali alqarni

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