Recent Advances In Molecular Biology And pathophysiology Of Thalassemia

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Slide 1 :

RECENT ADVANCES IN MOLECULAR BIOLOGY, PATHO-PHYSIOLOGY & TREATMENT OF THALASSEMIA

Slide 2 :

REFERENCES FOR THE PRESENTATION WINTROBE’S CLINICAL HEMATOLOGY 10TH EDITION VOLUME – I BY G. RICHARD, JOHN FORESTER, JOHN LUKKENS, FRIXOS PARASKEVAS, JOHN P. GREEN & GEORGE M RODGERS De GRUCHY’S CLINICAL HEMATOLOGY IN MEDICAL PRACTICE 5TH EDITION EDITED BY FRANK FIRKIN, COLIN CHESTERMAN, DAVID PENINGTON & BAYAN RUSH

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THALASSEMIA IN GREEK – SEA THALASSEMIA PATIENTS BEING OF MEDITERRANEAN BACKGROUND DEFINITION A heterogeneous group of disorders with a genetically determined reduction in the rate of synthesis of one or more normal hemoglobin polypeptide chain.

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THALASSEMIA -HISTORY PRE 1925 – NOT RECOGNISED AS A CLINICAL ENTITY IN 1925 THOMAS COOLEY (A DETROIT PEDIATRICIAN) HIGHLIGHTED A SYNDROME AMONGST ITALIAN CHILDREN CHARACTERISED BY PROFOUND ANEMIA SPLEENOMEGALY BONY DEFORMITIES

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PREVIOUS CLASSIFICATION OF THALASSEMIAS BASED ON CLINICAL SEVERITY MAJOR SEVERE ANEMIA TRANSFUSION DEPENDANCY LIFE LIMITING COMPLICATIONS OF IRON OVERLOAD INTERMEDIA LESS SEVERE HEMOLYTIC ANEMIA CHRONIC TRANSFUSION NOT REQUIRED SURVIVAL INTO ADULT LIFE

Slide 6 :

PREVIOUS CLASSIFICATION OF THALASSEMIAS BASED ON CLINICAL SEVERITY MINOR ASYMPTOMATIC CARRIER STATE DISORDER MORPHOLOGICAL CHANGES IN RED CELLS WITH LITTLE OR NO ANEMIA MINIMA UNDETECTABLE DETECTED ONLY THROUGH FAMILY STUDIES

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PRESENT CLASSIFICATION OF THALASSEMIAS a THALASSEMIA ß THALASSEMIA d THALASSEMIA d ß THALASSEMIA ? d ß THALASSEMIA

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HEREDITARY PERSISTENCE OF FETAL Hb (HPFH) CLOSELY RELATED GROUP OF DISORDERS DECREASED ß-GLOBIN SYNTHESIS COMPENSATED BY ? – GLOBIN PRODUCTION TYPES BLACK HPFH GREEK HPFH Hb KENYA HETROCELLULAR HPFH

Slide 9 :

PREVALANCE & GEOGRAPHIC DISTRIBUTION OF a AND ß THALASSEMIA PREPARED BY HERMANN LEHMANN 3% WORLD POPULATION (150 MILLION) CARRY ß–THALASSEMIA GENE MEDITERRANEAN BASIN MIDDLE EAST INDIAN SUB-CONTINENT MYANMAR

Slide 10 :

STRUCTURAL ORGANISATION OF THE HUMAN GLOBIN GENES GENES FOUND IN THE SAME ORDER INEMBRYONIC, FETAL & POST NATAL DEVELOPMENTAL STAGES

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STRUCTURE OF GLOBIN GENES

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THALASSEMIA & MOLECULAR BIOLOGY

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MOLECULAR BIOLOGY – FACTS ABOUT THALASSEMIA GENE DELETION RESULTS IN TO a - THALASSEMIA SYNDROME ONE OR MORE NUCLEOTIDE SUBSTITUTION OR DELETION IN INTACT GENES CAUSES ß- THALASSEMIA SYNDROME MUTATION RATE OF SINGLE BASES IN GLOBIN GENES ----- 1 IN 104 INDIVIDUAL / GENERATION DENOVO MUTATION RATE OF ß - CHAIN VARIANTS 7.4 X 10 + 9 PER ß - GENE NUCLEOTIDE PER GENERATION

Slide 14 :

TRANSVERSION vs TRANSITION IN PROTEIN STRUCTURE - AMINO ACID CHANGES BY TRANSVERSION MORE RADICAL - PURINE TRANSITION MORE COMMON THAN PYRIMIDINE TRANSITION - MOST COMMON POINT SUBSTITUTION - ADENING TO GUANINE IN DNA - GUANINE TO ADENINE IN RNA - IN SUBSTITUTION EFFECTING MOLECULAR SURFACE. RATIO OF TRANSVERSION : TRANSITION :: 2:1 - TRANSVERSION RARELY PRODUCES MOLECULAR CORE CHANGES

Slide 15 :

a- THALASSEMIA – MOLECULAR FACTS - MAJOR VARIANTS - a THALASEMIA 1 (a o) - a THALASSEMIA 2 (a +) - NON DELETION MUTATION LESS COMMON - OTHER NON DELETION MUTATIONS - ABNORMAL, UNSTABLE GLOBINS (THALASSEMIC HAEMOGLOBINOPATHIES) (GENO TYPE) (- -)

Slide 16 :

LEFT WARD DELETION PREVALANT IN SE ASIA & SAUDI ARABIA RARE IN BLACKS & MEDETERANIAN REGION

Slide 17 :

RIGHT WARD DELETION WORLD WIDE DISTRIBUTION AMONGST ALL RACIAL GROUPS

Slide 18 :

A UNIQUE CASE OF MUTATION - THREE NORTH EUROPEAN CHILDREN WITH - Hb H DISEASE - MENTAL RETARDATION - TWO CHILDREN HAD - RIGHT WARD DELETION - DENOVO DELITION OF ENTIRE a – GLOBIN GENE - THIRD BOY INHERITED RIGHT WARD DELETION FROM MOTHER & DE NOVO MUTATION FROM FATHER RESULTING IN INACTIVATION OF a- GENES

Slide 19 :

A UNIQUE CASE OF MUTATION FINDINGS LOCUS ADJACENT TO a–GENE CLUSTER WHEN CO-DELETED OR CO-MUTATED RESULTS IN MENTAL RETARDATION

Slide 20 :

a- THALASSEMIA SYNDROMES - HYDROPS FETALIS WITH Hb BART’S (- -/- -) - HbH DISEASE - a – THALASSEMIA MINOR - SILENT CARRIER STATE (- a /a a)

Slide 21 :

a- THALASSEMIA PREVALANCE - ALL FOUR SYNDROMES AMONGST ASIAN - HYDROPS FETAL IS WITH Hb BART’S RARE IN MEDITERRANEAN & NEVER REPORTED IN AFRICANS - HbH DISEASE RARE IN AFRICANS

Slide 22 :

ß- THALASEEMIA MOLECULAR FACTS - MAJOR VARIANTS - ß THALASSEMIA ß 0 - ß- THALASSEMIA ß+

Slide 23 :

ß- THALASSEMIA – TYPES OF MUTATION - SPLICE JUNCTION MUTATION - MUTANTS PRODUCING CONSENSUS CHANGES - MUTANTS CREATING NEW SPLICE SIGNALS - MUTANTS ENHANCING CRYPTIC SPLICE SITES - MUTANTS CAUSING DEFECTIVE CLEAVAGE - PROMOTOR REGION MUTATION - CHAIN TERMINATOR MUTATION - CAP SITE MUTATION

Slide 24 :

PATHO PHYSIOLOGY OF THALASSEMIAS

Slide 25 :

IMPACT OF THALASSEMIA ON RED CELL MEMBRANE - GLOBIN CONTENT OF RED CELL GHOSTS AND CYTO SKELETON IS INCREASED - MEMBRANE PHOSPHO LIPID AND CHOLESTEROL ARE INCREASED - MEMBRANE CATION FLUX INCREASES CAUSING NET LOSS OF K+ - MEMBRANE Ca++ CONTENT INCREASES - MEMBRANE RIGIDITY & VISCOSITY INCREASES -

Slide 26 :

IMPACT OF THALASSEMIA ON RED CELL MEMBRANE MECHANICAL STABILITY OF a – THALASSEMIC CELLS IS NORMAL OR SLIGHTLY INCREASED - MECHANICAL STABILITY OF ß THALASSEMIC CELLS IS MARKEDLY DECREASED - RED CELLS IN HbH DESEASE LESS DENSE THAN NORMAL RBCs - ß- THALASSEMIC RED CELLS HAVE BROAD DENSITY DISTRIBUTION

Slide 27 :

RED CELL DESTRUCTION - IN THALASSEMIA - SUSCEPTIBLE TO AUTO OXIDATION BECAUSE OF UNSTABLE GLOBIN GENES - EXCESSIVE INTRA CELLULAR IRON - SIALIC ACID RESIDUES REDUCED IN NUMBER AND DISTRIBUTED UNEVENLY ON SURFACE OF THALASSEMIC CELLS - INCREASE IN MEMBRANE IgG CAUSING INCREASED PHAGOCYTOSIS OF THALASSEMIC CELL (AS SEEN IN MOUSE)

Slide 28 :

FINDINGS IN THALASSEMIA PATIENTS HETROGENEITY OF RED CELL SURVIVAL IN ß- THALASSEMIA - CELL CONTAINING HbA ARE SHORT LIVED - CELLS CONTAINING HbF SURVIVE LONGER - CELL CENTRIFUGATION – YOUNGER CELLS CONTAIN HIGH PROPORTION OF HbA & ARE LESS DENSE - OLD CELLS CONTAIN HbF & ARE MORE DENSE - CELLS WITH HbF SHOW FEW OR NO INCLUSIONS - CELLS WITH LITTLE HbF SHOW MORE INCLUSIONS

Slide 29 :

FINDINGS IN ß -THALASSEMIA PATIENTS - CLINICAL SEVERITY OF HOMOZYGOUS ß- THALASSEMIA IS A FUNCTION OF ? : a SYNTHETIC RATIO OF BONE MARROW CELLS - HIGH RATIO INDICATIVE OF THALASSEMIA INTERMEDIA - LOW RATIO INDICATIVE OF THALASSEMIA MAJOR - RBCs SHORT LIVED CAUSING - INCREASED ERYTHROPOIESIS - 10 TIMES MORE THAN NORMAL IN THALASSEMI A - BONE DEFORMITIES - HEPATOMEGALY - SPLEENOMEGALY - CARDIOMEGALY -

Slide 30 :

FINDINGS IN THALASSEMIA PATIENTS - ANEMIA - SHORT RED CELL SURVIVAL - REDUCED HAEMOGLOBIN PRODUCTION - ABNORMAL HEME SYNTHESIS - INCREASED IRON ACCUMULATION IN NORMOBLAST MITOCHODRIA INHIBITS MITO CHONDRIAL ENZYMES CAUSING REDUCED HEME SYNTHESIS

Slide 31 :

CLINICAL & LAB FEATURES OF THALASSEMIA - a – THALASSEMIA SYNDROMES - HYDROPS FETALIS WITH Hb BART’S - HbH DISEASE - a- THALASSEMIA MINOR - SILENT CARRIER STATE

Slide 32 :

CLINICAL & LAB FEATURES OF THALASSEMIA HbH DISEASE

Slide 33 :

CLINICAL & LAB FEATURES OF THALASSEMIA HbH DISEASE

Slide 34 :

CLINICAL & LAB FEATURES OF THALASSEMIA a- THALASSEMIA MINOR

Slide 35 :

ß- THALASSEMIA SYNDROMES ß- THALASSEMIA MAJOR (COOLEY ANEMIA) SEVERE ANEMIA TRANSFUSION DEPENDANCY LIFE LIMITING COMPLICATIONS OF IRON OVERLOAD

Slide 36 :

ß- THALASSEMIA SYNDROMES THALASSEMIA INTERMEDIA THALASSEMIA MINOR THALASSEMIA MINIMA HB LEPORE SYNDROME THALASSEMIA MINOR

Slide 37 :

ß- THALASSEMIA IN ASSOCIATION WITH ß – CHAIN STRUCTURAL VARIANTS - HbS THALASSEMIA SYNDROME - HbS – ß THALASSEMIA - HbS d ß THALASSEMIA - Hb SHPFH - HbC THALASSEMIA - HbE THALASSEMIA

Slide 38 :

TREATMENT OF THALASSEMIA - TRANSFUSION THERAPY - SPLENECTOMY - IRON CHELATION - BONE MARROW TRANSPLATION - NEW APPROACHES

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Thalassemias are a heterogenous group of hereditary group of red blood cell disorders.
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