Presentation on theme: "GENETIC DISORDER OF HAEMOGLOBIN"— Presentation transcript:
1 GENETIC DISORDER OF HAEMOGLOBIN Haemoglobinopathies and Thalassaemias
2 HaemoglobinA conjugated protein consisting of iron-containing heme and protein (globin)Globin chains are of different types:-chains and non -chainsEach 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.
7 Hemoglobinopathy; definition An inherited mutation of the globin genes leading to a qualitative or quantitative abnormality of globin synthesis.
8 Structural hemoglobinopathy Amino acid substitution in the globin chain e.g. sickle hemoglobin (HbS)
9 The ThalassemiasSyndromes in which the rate of synthesis of a globin chain is reduced:-beta thalassemia – reduced beta chain synthesisalpha thalassemia – reduced alpha chain synthesis
10 Disorders of Haemoglobin Thalassaemias(Biosyntheticdisorderof Hb)Co-existingstructural /biosyntheticdisordersHaemoglobinopathies(Structural disorderof Hb)Constitute a major health problem in severalpopulations of the world(particularly those residing in malariaendemic region)
11 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 solubilityReduced stabilityAltered oxygen affinity- increased or decreasedMethaemoglobin formation
12 Hemoglobinopathies Decrease, lack of, or abnormal globin May be severe hemolytic anemiaAbnormal Hb with low functionalityMutation may be deletion, substitution, elongationHb electrophoresis may be helpful
13 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 genesUnequal 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.
14 Geographical distribution of common Hb variants Variant Occurrence predominantly in:Hb S (6GluVal) Africa, Arabia, Black AmericansHb C (6Glulys) West Africa, ChinaHb E (26Glulys) South East AsiaHb D (121GluGln) AsiaHb O (121GluVal) Turkey and Bulgury
18 Major abnormalities & problems in SCA Sickling of the red cell during deoxygenation, as the HbShas low solubility at low O2 partial pressure and precipitates.Chronic haemolytic anaemia due to repeated sickling in tissues andunsickling in the lungs.Plugging of microcapillaries by rigid sickled cells leading to sickle cellcrises i.e severe pain and edema. This causes significant damage tointernal 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 andfeet may be the first signs of sickle cell anemia in babies. The swelling iscaused by sickle-shaped red blood cells blocking blood flow out of theirhands and feetBone deformation – bossing of the forehead.Hepato-spleenomegaly.Growth retardation.Frequent blood transfusion requirements.Psychosocial problems.
19 Clinical Features Management Site of SicklingClinical FeaturesManagementBonePainful crisesPain relief and hydration. HydroxyureaLungAcute chest syndromeTransfusion regimen, pain relief and hydrationBrainStrokeTransfusion regimen.HeartMyocardial infarctionSpleenAcute splenic sequestration:Transfusion, pain relief and hydrationRetinaProliferative retinopathyRetinal surveillance. Laser
20 Sickle Cell Trait Heterozygous state for HbS (HbAS) No serious clinical consequencesSudden death during intensive trainingHematuria, isosthenuria (renal papillary necrosis)
21 Thalassaemias Genetic disorders resulting from decreased biosynthesis of globin chainsof haemoglobin.
22 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.
23 Types of Thalassaemias * Most common- Thalassaemia
24 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
29 - 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.
30 - Thalassaemia-1 Two -genes deletion- (o ) thal. The patient synthesizes -chain but it is decreased to about 50% of normal.Anaemic symptoms- hypochromic microcytic anaemia.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.
31 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.
32 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, severe hypochromic- microcytic anaemia.
33 Hb - Thalassaemia - Thalassaemia Increased / ratio In - ThalassaemiaDecreasedproductionof - chainsNormal = - ThalassaemiaAccumulation of
34 Beta thalassemia Impaired production of beta chain beta thalassemia minor – heterozygous (or trait)beta thalassemia major - homozygous
35 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.Major -usually appears in an infant after three months of age and causes life-threatening anemia35
36 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.
38 Beta thalassemia trait No symptomsMild microcytic anemia
39 Beta thalassemia major No beta chain produced (no HbA)Severe microcytic anemia occurs gradually in the first year of lifeMarrow expansionIron overloadGrowth failure and death
40 - 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 anemOften 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 Hb; (HPFH).
41 - ThalassaemiaIt 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 HbFlevel is increased.Majority of -thalassaemia is due to point mutation.
42 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.
44 Clinical Classification of Thalassaemias Thalassaemia major:The patient depends on blood transfusions especially if he is homozygous.Thalassaemia intermediate:Homozygous mild +-thalassaemia.Co-inheritance of -thalassaemia.Heterozygous -thalassaemia.Co-inheritance of additional -globin genes. -thalassaemia and hereditary persistence of foetal HbHomozygous Hb leporeHb H disease.3. Thalassaemia minor (trait):o-thalassaemia trait.+-thalassaemia trait.Hereditary persistence of foetal Hb only.-thalassaemia trait.o- and +-thalassaemia trait.
45 Beta thalassemia major treatment TransfusionIron chelationStem cell transplant
46 Hb-LeporeThis 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 11GA5’3’
47 Hemoglobinopathy-antenatal diagnosis Test partners of heterozygous or affected individualsAntenatal diagnosis from DNA obtained by chorionic villus sampling, or by amniocentesis