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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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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
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.
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
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
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
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.
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.
DIAGNOSIS • Sickling test • Electrophoresis
THALASSEMIAS • Autosomal recessive disorders • Gene function is abnormal. • TYPES: • (a) Thalassemias - chain • (b) Thalassemias - chain
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
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.
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.
LABORATORY DIAGNOSIS OF HAEMOGLOBINOPATHIES • Hb%, Full blood count • Peripheral blood film • Electrophoresis • Peptide analysis • DNA finger printing technique