Thalassemia.ppt

April 2, 2018 | Author: YASSER2009FREE | Category: Anemia, Medical Genetics, Hemoglobin, Genetic Disorder, Hematology


Comments



Description

Thalassemias1 HEMOGLOBIN A α β β α  Fetal Hemoglobin (2 alpha, 2 gamma)  Hemoglobin A2 (2 alpha, 2 delta)  Small amounts in body Disorders of Haemoglobin 1. Thalassemia 2. Haemoglobinopathies What is Thalassaemia ? Thalassaemia is a group of inherited disorders of hemoglobin synthesis characterized by a reduced or absent one or more of the globin chains of adult hemoglobin . Genetic autosomal recessive blood disease. The name is derived from the Greek words Thalasso = Sea" and "Hemia = Blood" in reference to anemia of the sea. Thalassemia ► Mediterranean Anemia’- 1st published in 1925 ► May be either homozygous defect or heterozygous defect. 5 Thalassemia ► Results in overall decrease in amount of hemoglobin produced and may induce hemolysis. ► May contribute protection against malaria. 6 Demographics: Thalassemia • Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma GeneticTypes of Thalassaemia : There are two basic groups of thalassaemia.  Alpha (  )Thalassaemia  Beta (  )Thalassaemia Clinical Types of Beta Thalassaemia : There are 3 types of Beta thalassaemia : 1. Thalassaemia Minor 2. Thalassaemia Intermediate 3. Thalassaemia Major Genetics of Thalassemia ► Adult hemoglobin composed two alpha and two beta chains. ► Alpha thalassemia usually caused by gene deletion; Beta thalassemia usually caused by mutation. ► Results in microcytic, hypochromic anemias of varying severity. 10 Normal Human Haemoglobins Haemoglobin Structural formula Adult Hb-A Hb-A2 2 2 97% 2 2 1.5-3.2% Fetal Embryonic Hb-F Hb-Gower 1 Hb-Gower 2 Hb-Portland 2 2 2 2 2 2 2 2 0.5-1% Chromosomes Gene Structure ( Alpha 1 and Alpha 2 produce identical chains) ALPHA THALASSEMIA  Alpha Thalassemia: deficient/absent alpha subunits    Excess beta subunits Excess gamma subunits newborns Tetramers formed: Hemoglobin H adults  Hemoglobin Bart’s newborns β/γ β/γ   Five types:      Silent Carrier Trait (Minor) Hemoglobin H Disease Major (Hemoglobin Bart’s) Hemoglobin Constant Spring β/γ β/γ GENETIC BASIS OF ALPHA THALASSEMIA Encoding genes on chromosome 16 (short arm)  Each cell has 4 copies of the alpha globin gene    Each gene responsible for ¼ production of alpha globin 4 possible mutation states: Loss of ONE gene  silent carrier  Loss of TWO genes  thalassemia minor (trait)  Loss of THREE genes  Hemoglobin H  Accumulation of beta chains  Association of beta chains in groups of 4  Hemoglobin H   Loss of FOUR genes  Hemoglobin Barts NO alpha chains produced ∴ only gamma chains present  Association of 4 gamma chains  Hemoglobin Barts  Classification & Terminology Alpha Thalassemia • Normal • Silent carrier • Minor • Hb H disease • Barts hydrops fetalis / - / -/- --/ --/- --/-- CLINICAL OUTCOMES OF ALPHA THALASSEMIA  Silent carriers • asymptomatic • “normal”  Alpha Thalassemia minor (trait) • no anemia • microcytosis -unusually small red blood cells due to fewer Hb in RBC • “normal”  Alpha Thalassemia intermedia (“Hemoglobin H”) • microcytosis & hemolysis (breakdown of RBC) - results in severe anemia • bone deformities • splenomegaly (enlargement of spleen) • “severe and life threatening” CLINICAL OUTCOMES OF ALPHA THALASSEMIA  Alpha Thalassemia major Hb Bart’s • fatal hydrops fetalis - fluid build-up in fetal compartments, leads to death • • occurs in utero BETA THALASSEMIA  Beta Thalassemia: deficient/absent beta subunits   Commonly found in Mediterranean, Middle East, Asia, and Africa Three types: Minor  Intermedia  Major (Cooley anemia)   May be asymptomatic at birth as HbF functions GENETIC BASIS OF BETA THALASSEMIA Encoding genes on chromosome 11 (short arm)  Each cell contains 2 copies of beta globin gene    beta globin protein level = alpha globin protein level Suppression of gene more likely than deletion  2 mutations: beta-+-thal / beta-0-thal “Loss” of ONE gene  thalassemia minor (trait)  “Loss” of BOTH gene  complex picture  2 beta-+-thal  thalassemia intermedia / thalassemia major  2 beta-0-thal  thalassemia major  beta-+-thal / beta-0-thal  thalassemia major   Excess of alpha globin chains Classification & Terminology Beta Thalassemia • Normal • Minor • Intermedia • Major / /0 /+ 0/+ +/+ 0/0 +/+ 0/+ CLINICAL OUTCOMES OF BETA THALASSEMIA  Beta Thalassemia minor (trait) • • •  Beta Thalassemia intermedia •  asymptomatic microcytosis minor anemia symptoms similar to Cooley Anemia but less severe Beta Thalassemia major (Cooley Anemia) • • • • • • • most severe form moderate to severe anemia intramedullary hemolysis (RBC die before full development) peripheral hemolysis & splenomegaly skeletal abnormalities (overcompensation by bone marrow) increased risk of thromboses pulmonary hypertension & congestive heart failure Thalassemia major Thalassemia minor Pathophysiology Disturbance of ratio between Alpha & non alpha globin chain synthesis then absent or decrease production of one or more globin chains  Formation of abnormal Hb structures  Ineffective erythropoiesis  Excessive RBCs Destruction  Iron Overload  Extra-medullary hematopoiesis  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. Laboratory Diagnosis of Thalassemia 36 Laboratory Diagnosis         Thalassemia minor: Haemoglobin : Haemoglobin level is usually normal or mildly reduced. Peripheral blood film : Hypochromia and Microcytosis (similar to Iron Deficiency Anemia). MCV< 75 fl, RDW < 14%. Reticulocyte Count increases Decrease Osmotic Fragility Haemoglobin electrophoresis HPLC (High Performance liquid chromatography) Haemoglobin electrophoresis A F S C Other Special Procedures ► Globin Chain Testing - determines ratio of globin chains being produced. ► DNA Analysis - Determine specific defect at molecular DNA level. 41 Course and treatment of thalassaemia Untreated  thalassemia Major : Death in first or second decade of life  Intermedia: variable life span  Minor/Minima: Normal life span TREATMENTS FOR ALPHA THALASSEMIA Silent Carrier – no treatment required  Trait (Minor) – no treatment required  Hemoglobin H Disease – Folate    avoid iron supplements Major (Hemoglobin Bart’s) –RBC transfusion while still in womb, else fetus is stillborn or dies shortly TREATMENT FOR BETA THALASSEMIA Trait – no treatment required  Intermedia  Major (Cooley anemia)  Regular folate supplementation  RBC transfusion (Splenectomy may decrease need for transfusions)  to maintain [Hgb] ~9-10g/dL  Blood transfusions  iron accumulation  iron overload  Iron chelators (diferroxamin) 
Copyright © 2024 DOKUMEN.SITE Inc.