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Hemoglobin metabolism & diseases of hemoglobin

Hemoglobin metabolism & diseases of hemoglobin. T & R form of Hb. Co-operative binding of oxygen. Binding of oxygen Mb Vs Hb. Transport of carbondioxide. Transport of carbondioxide. Bohr’s effect. Hemoglobinopathies.

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Hemoglobin metabolism & diseases of hemoglobin

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  1. Hemoglobin metabolism & diseases of hemoglobin

  2. T & R form of Hb

  3. Co-operative binding of oxygen

  4. Binding of oxygen Mb Vs Hb

  5. Transport of carbondioxide

  6. Transport of carbondioxide

  7. Bohr’s effect

  8. Hemoglobinopathies • Hemoglobinopathies are the disorders caused by the synthesis of abnormal hemoglobin or insufficient production of normal hemoglobin or rarely both • Sickle cell hemoglobin:-abnormal hemoglobin • Thallasemias:-insufficient synthesis of hemoglobin

  9. Sickle cell hemoglobin

  10. DEFINITION: When biological function is altered due to mutation in hemoglobin. CAUSES: (a) Mutation in structural gene  Abnormalities in the primary sequence of globin chain. Exp. Hb-S, Hb-M, Hb-C, Hb-D, etc. (b) Mutation in regulatory gene  Abnormalities in rate of synthesis. Exp. Thalassemias. 95% (single gene mutation/ point mutation) & others – frame shift mutation & terminator codon mutation • EFFECT OF ABNORMAL HAEMOGLOBIN: • Abnormalities in red cell morphology. • Clinical manifestation  haemolytic anaemia/ jaundice.

  11. Genetic control of Hb synthesis  2 1 chrom 16  like gene  G A   chr-11  like gene Normally synth of  &  ( in fetus) is carefully balance  correct tetramer assembly

  12. TYPES: (a) Quantitative/ Structural gene defect E.g. Sickle cell anaemia (b) Qualitative/ Regulatory gene defect E.g. Thalassaemias ( & ) • STRUCTURAL HAEMOGLOBIN VARIANTS • Replacement/ alteration of single AA • Insertion/ deletion of AA or • Polypeptide fusion

  13. SICKLE CELL ANAEMIA (HbS) • > 60 million carrier & 100,000 affected infant annually • Homozygous inheritance disorder PATHOPHYSIOLOGY: GENETIC DEFECT: Point/Frame shift GAG  GUG [Glu acid  valine] on 6th position of  chain of globin  HbS

  14. BIOCHEMICAL EXPLANATION OF SICKLING • Glu (Hydrophilic/Polar)  Valine (hydrophobic/non-polar) • Less negative charge than HbA (Hb surface charge). •  localized stickiness on surface of  chain. •  deoxygenated HbS  sticky patch bind with complementary patch  polymerisation. •  intracellular fibres are formed. •  distortion of cells into sickle shaped. PREVENTION OF SICKLING: • Hb in oxygenated form or  Deoxy Hb. TYPES: • (a) Homozygous – 80-100% HbS & 0-20% HbA. • (b) Heterozygous – may be asymptomatic 20-40% HbS & 60-80% HbA.

  15. SYMPTOMS: • Anaemia (6 – 8g/dL) • RBC more fragile (10 – 15 days) • Cells are rigid solubility  obstruct the flow  vasoocclusion  tissue hypoxia. • Extreme pain & tissue death. • Susceptible to infection. RELATIONSHIP WITH OTHER DISEASES • Protection from malaria. •  incidence to salmonella infection.

  16. DIAGNOSIS • Sickling test • Electrophoresis

  17. THALASSEMIAS • Autosomal recessive disorders • Gene function is abnormal. • TYPES: • (a)  Thalassemias -  chain • (b)  Thalassemias -  chain

  18. THALASSEMIAS •  synth/ total absence of  globulin • involve the genes HBA1& HBA2 and forms 4  THALASSEMIA •  synth / total absence of  globin chain  (4) or toxic aggregates

  19. GENETICS: Defect in mRNA for affected globin chain (quantitative/ qualitative) • DEFECTS: • Operator gene/ Regulator gene defect. • Lowered stability of mutant mRNA. • Loss of start signals for translation of mRNA. • Non-sense mutations lead to premature chain termination. • Abnormal post transcriptional processing • Rapid degradation of highly unstable globin chain.

  20. Types of  Thalassemia – Four types

  21. Types of  Thalassemia – two types (a)  Thalassemia MINOR ( Thalassemia Trait) • Heterozygous state – defect in only one  globulin gene • Common in USA. • Usually asymptomatic. (b)  Thalassemia MAJOR • Homozygous state (both gene) • At birth baby is healthy • After birth severe anemic & die 1-2 yrs.

  22. LABORATORY DIAGNOSIS OF HAEMOGLOBINOPATHIES • Hb%, Full blood count • Peripheral blood film • Electrophoresis • Peptide analysis • DNA finger printing technique

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