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GENETIC DISORDER OF HAEMOGLOBIN Haemoglobinopathies and Thalassaemias 1 Haemoglobin A conjugated protein consisting of iron-containing heme and protein (globin) Globin chains are of different types: -chains and non -chains Each molecule is a tetramer of two - and non chains. Each globin binds a haem in a haem binding site. Haemoglobin binds and transports oxygen from lungs to the tissues, while it transports CO2 from tissues to the lungs. 2 3 Types of Hemoglobin in adults Globin genes in Chromosome 16 11 Gene product Tetramers Name of Conc. (globin)in RBCs haemoglobin adult , -chain 2 2 Hb A 96-97 , -chain 2 2 Hb A2 2.3-3.5 Hb F <1.0 ,-chain 2 2 ----------------------------------------------------------------- 4 Chromosome 11 5’ G A 3’ Chromosome 16 2 1 2 1 5’ 3’ Structure of each Globin gene 5’ Exon 1 Intron 1 Exon 2 Intron 2 3’ Exon 3 5 HEMOGLOBIN SYNTHESIS 25% 25% 0.5% 1.5% 48% α α γ δ β α α γ δ β 25% 25% 0.5% 1.5% 48% Chromosome 16 Chromosome 11 6 HEMOGLOBINOPATHY; DEFINITION An inherited mutation of the globin genes leading to a qualitative or quantitative abnormality of globin synthesis. 7 STRUCTURAL HEMOGLOBINOPATHY Amino acid substitution in the globin chain e.g. sickle hemoglobin (HbS) 8 THE THALASSEMIAS Syndromes in which the rate of synthesis of a globin chain is reduced: beta thalassemia – reduced beta chain synthesis alpha thalassemia – reduced alpha chain synthesis 9 Disorders of Haemoglobin Haemoglobinopathies (Structural disorder of Hb) Thalassaemias (Biosynthetic disorder of Hb) Co-existing structural / biosynthetic disorders Constitute a major health problem in several populations of the world (particularly those residing in malaria endemic region) 10 Haemoglobinopathies • • • • Genetic structural disorder. Due to mutation in the globin gene of haemoglobin. Mostly autosomal recessive inheritance. Result in haemoglobin variants with altered structure and function. • Altered functions include: Reduced solubility Reduced stability Altered oxygen affinity- increased or decreased Methaemoglobin formation 11 HEMOGLOBINOPATHIES Decrease, lack of, or abnormal globin May be severe hemolytic anemia Abnormal Hb with low functionality Mutation may be deletion, substitution, elongation Hb electrophoresis may be helpful 12 Types of Mutations in Haemoglobin • Point mutation: a change of a single nucleotide base in a DNA giving rise to altered amino acids in the polypeptide chains (e.g. Hb S , Hb C) • Deletions and additions: Addition and deletion of one or more bases in the globin genes • Unequal crossing over: as in Hb-lepore and Hb-antilepore associated with -thalassaemias. ________________________________________________________ *Most abnormal Hbs are produced by mutations in the structural genes which determine the amino acid sequence of the globin chains of the Hb molecule. 13 Geographical distribution of common Hb variants Variant Occurrence predominantly in: Hb S (6GluVal) Africa, Arabia, Black Americans Hb C (6Glulys) West Africa, China Hb E (26Glulys) South East Asia Hb D (121GluGln) Hb O (121GluVal) Asia Turkey and Bulgury 14 Sickle Cell Haemoglobin GAG 6 RBC GTG Sickle Cell 15 Haemolysis Inheritance of Sickle Cell Anaemia AR AS AS AS SS AA AS 16 Red cell sickling Lungs ↑pO2 Tissues ↓pO2 17 Major abnormalities & problems in SCA Sickling of the red cell during deoxygenation, as the HbS has low solubility at low O2 partial pressure and precipitates. Chronic haemolytic anaemia due to repeated sickling in tissues and unsickling in the lungs. Plugging of microcapillaries by rigid sickled cells leading to sickle cell crises i.e severe pain and edema. This causes significant damage to internal organs, such as heart, kidney, lungs and endocrine glands. Repeated infections. Frequent cerebrovascular accidents. Hand-foot syndrome (in small,i.e.around age of 3y); Swollen hands and feet may be the first signs of sickle cell anemia in babies. The swelling is caused by sickle-shaped red blood cells blocking blood flow out of their hands and feet Bone deformation – bossing of the forehead. Hepato-spleenomegaly. Growth retardation. 18 Frequent blood transfusion requirements. Psychosocial problems. Site of Sickling Clinical Features Management Bone Painful crises Lung Acute chest syndrome Stroke Myocardial infarction Acute splenic sequestration: Proliferative retinopathy Pain relief and hydration. Hydroxyurea Transfusion regimen, pain relief and hydration Transfusion regimen. Transfusion regimen, pain relief and hydration Transfusion, pain relief and hydration Retinal surveillance. Laser Brain Heart Spleen Retina 19 SICKLE CELL TRAIT Heterozygous state for HbS (HbAS) No serious clinical consequences Sudden death during intensive training Hematuria, isosthenuria (renal papillary necrosis) 20 Thalassaemias Genetic disorders resulting from decreased biosynthesis of globin chains of haemoglobin. 21 Thalassaemias • • • • A group ( not single identity) of Genetic defects. Due to mutations in and around the globin genes. Decreased production of one or more of the globin chains. Result in an imbalance in the relative amounts of the - and non -chains. Altered /non- ratio. • As a consequences of thalassaemias there is excess production of the other chains, and a decreased over all haemoglobin synthesis. 22 Types of Thalassaemias - Thalassaemia* -Thalassaemia* - Thalassaemia - Thalassaemia - Thalassaemia 23 * Most common α Thalassemia Deletion of one or more alpha genes from chromosome 16 -a/aa: silent career with little signs --/aa: cis double deletion more common in SEA -a/-a: trans double deletion --/-a: Hb H disease --/--: Hb Bart’s hydrops fetalis 24 ALPHA THALASSEMIA αα/αα Normal αα/α- Mild microcytosis αα/- α-/αα-/- - Mild microcytosis - -/- - Hemoglobin Barts – Hydrops Fetalis Hemoglobin H disease 25 - Thalassaemia - Decreased / ratio Hb In - Thalassaemia Decreased production of - chains Normal = - Thalassaemia Accumulation of 26 Point Mutation producing - Thalassaemia Less Frequent Introns Chromosome 16 5’ exon1 exon2 3’ exon3 Base Substitution 2bp del 5bp del Chain Termination Defect Poly A signal Mutation 27 Mutations Producing - Thalassaemia Deletions Most frequent: Chromosome 16 / Normal -/ -/- --/ --/- --/-- -thal 2 -thal 2 -thal 1 HbH Hydrops hetero homo hetero Disease fetalis 28 - Thalassaemia-2 • One -gene deletion. • -chain production is only about 75% of normal. • May be homo- (- /- ) or heterozygous (- / ) • The patient usually shows a normal phenotypic appearance but there might be mild thalassaemia symptoms. • Hypochromic-microcytic RBC’s due to partial reduction of -chain. 29 - Thalassaemia-1 • Two -genes deletion- (o ) thal. • The patient synthesizes -chain but it is decreased to about 50% of normal. • Anaemic symptomsanaemia. • May be homozygous (- -/- -) or heterozygous(--/ ). If the patient is homozygous than there is no -chain synthesis, and if heterozygous then there is decreased synthesis of the -chain to half normal level. hypochromic microcytic 30 Hb H Disease • Three -gene (three alleles) deletion. • The Hb present during foetal life is “Hb Bart’s” (4), while during adulthood the Hb present is “Hb H” (4). • Some of the symptoms include: hepatosplenomegaly, impairment of erythropoiesis, and hypochromic-microcytic haemolytic anaemia. 31 Hydrops foetalis • Homozygous o-thalassaemia. • There is a complete absence of -chain (all -genes are deleted). • The Hb produced at birth is Hb Barts (4). • • Hydrops foetalis is lethal and the baby is born dead. Hydrops fetalis is a severe, life-threatening problem of severe edema (swelling) in the fetus and newborn. It is also called hydrops. • Symptoms include: Hepatosplenomegaly, hypochromic- microcytic anaemia. severe 32 - Thalassaemia Increased / ratio Hb In - Thalassaemia Decreased production of - chains Normal = - Thalassaemia Accumulation of 33 BETA THALASSEMIA Impaired production of beta chain beta thalassemia minor – heterozygous (or trait) beta thalassemia major - homozygous 34 TYPES OF - THALASSAEMIA Thalassemia Major (Cooley's anemia) -severe form of beta thalassemia - presence of two abnormal genes that cause either a severe decrease or complete lack of beta globin production. Thalassemia Minor - presence of one normal gene and one with a mutation - causes mild to moderate mild anemia. ETIOLOGY OF - THALASSAEMIA Beta thalassemia is caused by a deficiency of Beta globin inherited in an autosomal recessive pattern, which means both copies of the HBB(Hemoglobin beta) gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. BETA THALASSEMIA TRAIT No symptoms Mild microcytic anemia 38 BETA THALASSEMIA MAJOR No beta chain produced (no HbA) Severe microcytic anemia occurs gradually in the first year of life Marrow expansion Iron overload Growth failure and death 39 - Thalassaemia Usually point mutation in the control region. The absence of beta-globin is referred to as beta-zero (B0) thalassemia. Other HBB gene mutations allow some beta-globin to be produced but in reduced amounts. A reduced amount of beta-globin is called beta-plus (B+) thalassemia β+ has minimal production. β+/β+ or βo/βo is thal major or Cooley’s anem Often not apparent at birth until β chain takes over γ chain production. High Hb A2, Hb F. Related: Hb Lepore (δ-β usion), High Persistence of Foetal 40 Hb; (HPFH). - Thalassaemia • It is characterized by either no -chain synthesis (i.e. o) or decreased synthesis of -chain (+). • Excess -chains precipitate in RBC’s causing severe ineffective erythropoiesis and haemolysis. • The greater the -chains, the more severe the anaemia. • Production of -chains helps to remove excess -chains and to improve the -thalassaemia. Often HbF level is increased. • Majority of -thalassaemia is due to point mutation. 41 o-Thalassaemia The -chain is totally absent. There is increase in HbF with absence of HbA. This is combined with ineffective erythropoiesis. In majority of the cases, -gene is present but there is complete absence of mRNA. • Characteristics of this disorder are: • Skeletal deformities (e.g. enlargement of upper jaw, bossing of skull and tendency of bone fractures). • Severe hypochromic- microcytic anaemia. • Survival depends on regular blood transfusion. • This leads to iron overload (iron accumulates in the blood and tissues, causing tissue damage). • Death usually occurs in the 2nd decade of life (i.e. at age of about 20 years) if measures are not taken to avoid iron overload by chelation therapy. • • • • Mutations affecting the -Globin gene. Chromosome 11 1. 2. 3. 4. 5. Mutations affecting transcription initiation Mutations affecting RNA splicing Mutations affecting translation initiation Non-sense Mutations. Mutations of polyadenylation site. >200 -Thal mutations reported to-date Worldwide 43 Clinical Classification of Thalassaemias 1. Thalassaemia major: The patient depends on blood transfusions especially if he is homozygous. 2. Thalassaemia intermediate: • Homozygous mild +-thalassaemia. • Co-inheritance of -thalassaemia. • Heterozygous -thalassaemia. • Co-inheritance of additional -globin genes. • -thalassaemia and hereditary persistence of foetal Hb • Homozygous Hb lepore • Hb H disease. 3. Thalassaemia minor (trait): • o-thalassaemia trait. • +-thalassaemia trait. • Hereditary persistence of foetal Hb only. • -thalassaemia trait. 44 • o- and +-thalassaemia trait. BETA THALASSEMIA MAJOR TREATMENT Transfusion Iron chelation Stem cell transplant 45 Hb-Lepore • This is an abnormal Hb due to unequal crossing-over of the - and -genes to produce a polypeptide chain consisting of the - chain at its amino end and - chain at its carboxyl end. • The -fusion(hybrid) chain is synthesized inefficiently and normal and -chain production is abolished. • The homozygotes show thalassaemia intermediate and heterozygotes show thalassaemia trait. Chromosome 11 5’ G A 3’ HEMOGLOBINOPATHY-ANTENATAL DIAGNOSIS Test partners of heterozygous or affected individuals Antenatal diagnosis from DNA obtained by chorionic villus sampling, or by amniocentesis 47