Lecturer of Medical Biochemistry HEMOGLOBINOPATHIES Dr. Dalia Abdel-Wahab Lecturer of Medical Biochemistry and Molecular Biology

Intended learning outcomes (ILOs): Studying this chapter should enable you to: Define hemoglobinopathies List different types of hemoglobinopathies Explain the biochemical basis of sickle cell anaemia Explain the biochemical basis of Hemoglobin C disease & Methemoglobinemias Explain the biochemical basis of Thalassemias Identify the biochemical basis of β-Thalassemias Identify the biochemical basis of α-Thalassemias

HEMOGLOBINOPATHIES Hemoglobinopathies are family of genetic disorders caused by production of a structurally abnormal hemoglobin molecule, synthesis of insufficient quantities of normal hemoglobin, or, rarely, both.

Different types of HEMOGLOBINOPATHIES Qualitative hemoglobinopathy result from production of hemoglobin with an altered amino acid sequence Sickle cell anemia (Hb S), hemoglobin C disease (Hb C), hemoglobin SC disease (Hb S + Hb C) Quantitative hemoglobinopathy as thalassemias are caused by decreased production of normal hemoglobin

Glutamic Acid (polar negatively charged) Sickle cell anemia Sickle cell anemia is an Autosomal Recessive disease in which a mutation occurs at 6 th position in the two β- chains: Glutamic Acid (polar negatively charged) is changed into Valine (non charged)

Sickle cell anemia Being Autosomal Recessive disease, Symptoms occurs mainly in homozygous individuals (100% HBS ) Heterozygous individuals (trait) present symptoms only in Hypoxic conditions (50% HB A and 50% HBS)

Sickle cell anemia Sickle cell anemia is characterized by lifelong episodes of pain (“crises”), chronic hemolytic anemia with associated hyperbilirubinemia and increased susceptibility to infections, usually beginning in early childhood

This type of hemoglobin is called Hemoglobin S Sickle cell anemia This type of hemoglobin is called Hemoglobin S

HbS Polymerizes to form long filaments This causes sickling of cells

Factors that increase sickling They are all factors in favors of deoxygenated form of Hb: Acidosis Hypoxia Increase CO2 Increase 2,3 BPG

Factors that increase sickling The replacement of the charged glutamate with the nonpolar valine forms a protrusion on the β-globin that fits into a complementary site on the β chain of anoth hemoglobin molecule in the cell. At low oxygen tension, deoxyhemoglobin S polymerizes inside the RBC, forming a network of fibrous polymers that stiffen and distort the cell, producing rigid, misshapen erythrocytes.

Sickle cell anemia Sickle cell anemia offers advantage against malaria infection due to short life span of RBCs (10-15 days)

Hb electrophoresis at alkaline pH Normal Trait Anemia Hb A Hb S + -

Other types of hemoglobinopathies Hb M: substitution of proximal histidine by tyrosine causing oxidation of Fe++ to Fe+++ forming methemoglobin cannot bind oxygen “chocolate cyanosis” (a brownish-blue coloration of the skin and mucous membranes) and chocolate-colored blood Due to tissue hypoxia causing anxiety, headache, and dyspnea

Hb C: Substitution of two glutamate residues in the  chain by lysine casing mild hemolytic anemia This substitution causes Hb C to move more slowly toward the anode than Hb A or Hb S. Why?

“Decreased rate of synthesis of Thalassemias “Decreased rate of synthesis of globin chains”

There is defect in one or more of the 4 copies of -globin gene. -Thalassemias There is defect in one or more of the 4 copies of -globin gene. This results in decrease synthesis of -globin chains or their complete absence

Types of -Thalassemias Silent carrier: one -globin gene is defective -Thalassemia trait: two -globin genes are defective Hb H disease: three -globin genes are defective Hydrops fetalis: the four genes are defective (intrauterine fetal death occurs)

-Thalassemias Caused by a defect in one or in the two copies of -globin chains. There is decrease rate of synthesis of -globin chains.  or  chains will increase.

Types of -Thalassemias Thalassemia minor= -Thalassemia trait These are heterozygous individuals who inherit only one defective gene from one of their parents 2) Thalassemia major: Homozygous individuals who inherit two defective copies for the gene from both parents. They present with hemolytic anaemia.

MCQ Sickle cell anemia is caused by a mutation in hemoglobin that causes: 1) a change from a non-charged amino acid to a charged amino acid. 2) a change from a charged amino acid to a non-charged amino acid. 3) loss of a post-translational modification of an amino acid. 4) a failure to reduce Fe3+ to Fe2+. 5) dissociation of hemoglobin to dimers.

MCQ Thalassemia is caused by: 1) Absence or decrease of Hb S. 2) Presence of excessive amount of Hb A2. 3) Presence of an abnormal hemoglobin. 4) Defect in the synthesis of one or more of the polypeptide chains of hemoglobin.