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 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

Sickle cell 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  like gene chrom 16  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

Operator gene/ Regulator gene defect. 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 – Four types Missing gene Symptoms Silent carrier 1 No  Thalassemia 2 Mild anaemia Hemoglobin H Disease 3 Moderate anaemia Hydrofetalis 4 Severe form

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