Hemoglobinopaties

B.N

Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. Abnormal hemoglobins appear in one of three basic circumstances: Structural defects in the hemoglobin molecule: Mutations in the gene for one of the two hemoglobin subunit chains, alpha or beta. Often, mutations change a single amino acid building block in the subunit. Most commonly the change is innocuous. Occasionally, alteration of a single amino acid dramatically disturbs the behavior of the hemoglobin molecule and produces a disease state. Sickle hemoglobin exemplifies this phenomenon.

Diminished production of one of the two subunits of the hemoglobin molecule: Hemoglobin chain imbalance damages and destroys red cells thereby producing anemia. Mutations that produce this condition are termed thalassemias. Abnormal associations of otherwise normal subunits: A single subunit of the alpha chain and a single subunit from the beta-globin locus combine to produce abnormal hemoglobin dimer.

Hemolytic anemia

Hemolytic anemia is the general name for any type of anemia that occurs because red blood cells are being destroyed too quickly. Many different medical problems can cause hemolytic anemia, including:
Inherited abnormalities in the cell membrane of red blood cells, Inherited enzyme deficiencies inside red blood cells, Physical damage to red blood cells, An autoimmune response, Hypersplenism, Hemoglobin disorders

Sickle-cell disease

Introduction

Sickle cell anemia was the first genetic disease to be characterized at the molecular level. It is an autosomal recessive genetic blood disorder with incomplete dominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickle-cell disease, usually presenting in childhood, occurs more commonly in people (or their descendants) from parts of tropical and subtropical regions where malaria is or was common. One-third of all indigenous inhabitants of SubSaharan Africa carry the gene.

Sickle-cell disease

Hemoglobin S: The most common type of abnormal hemoglobin and the basis of sickle cell trait and sickle cell anemia. Hemoglobin S differs from normal adult hemoglobin (called hemoglobin A) only by a single amino acid substitution (a valine replacing a glutamine in the 6th position of the beta chain of globin). Recognition of this tiny change in the hemoglobin molecule marked the opening of molecular medicine.

Sickle-cell disease Pathophysiology

Normal red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. In sickle-cell disease, low-oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.

Sickle-cell disease Pathophysiology

The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells inside the spleen, because of their misshape. Healthy red blood cells typically live 90120 days, but sickle cells only survive 1020 days.

Normal red cells maintain their shape as they pass through the capillaries and release oxygen to the peripheral tissues (upper panel). Hemoglobin polymers form in the sickle rell cells with oxygen release, causing them to deform. The deformed cells block the flow of cells and interrupt the delivery of oxygen to the tissues (lower panel).

Sickle-cell disease

Genetics

Sickle-cell anaemia is caused by a point mutation in the -globin chain of haemoglobin, causing the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position. The -globin gene is found on the short arm of chromosome 11.

Approximate gene location is based on Chromosome 11 map from NCBI Entrez Map Viewer. Official Gene Symbol: HBB Name of Gene Product: hemoglobin, beta Alternate Name of Gene Product: beta globin Locus: 11p15.5 Gene Structure: The normal allelic variant for this gene is 1600 base pairs (bp) long and contains three exons. mRNA: The intron-free mRNA transcript for the HBB gene is 626 base pairs long. See the NCBI sequence record NM_000518 to access the mRNA sequence data. Coding Sequence (CDS): 444 base pairs within the mRNA code for the amino acid sequence of the gene's protein product. Protein Size: The HBB protein is 146 amino acids long and has a molecular weight of 15,867 Da.

Sickle-cell disease

Genetics

Hemoglobin consists of four protein subunits, typically, two subunits called alpha-globin and two subunits called betaglobin. The HBB gene provides instructions for making betaglobin. Various versions of beta-globin result from different mutations in the HBB gene. Normal hemoglobin called hemoglobin A. One particular HBB gene mutation produces an abnormal version of beta-globin known as hemoglobin S (HbS). Other mutations in the HBB gene lead to additional abnormal versions of beta-globin such as hemoglobin C (HbC) and hemoglobin E (HbE). HBB gene mutations can also result in an unusually low level of beta-globin; this abnormality is called beta

Sickle-cell disease

Genetics

In people with sickle cell disease, at least one of the beta-globin subunits in hemoglobin is replaced with hemoglobin S. In sickle cell anemia, hemoglobin S replaces both beta-globin subunits in hemoglobin. In other types of sickle cell disease, just one betaglobin subunit in hemoglobin is replaced with hemoglobin S. The other beta-globin subunit is replaced with a different abnormal variant, such as hemoglobin C. For example, people with sickle-hemoglobin C (HbSC) disease have hemoglobin molecules with hemoglobin S and hemoglobin C instead of betaglobin.

Sickle-cell disease

Epidemiology

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, India and the Middle-East. Africa: Sub-saharian around 2% of newborns in Nigeria and 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10% and 40% across equatorial Africa, decreasing to 12% on the north African coast and <1% in South Africa. Europe: France because migration of substantial populations from Africa. SCD has become the most common genetic disease in France.

Sickle-cell disease

Epidemiology

United Kingdom: more than 200 babies are born annually with SCD. Middle East: about 6,000 children are born annually with SCD, at least 50% of these in Saudi Arabia. India: Sickle cell disease is prevalent in many parts of India, where the prevalence has ranged from 9.4 to 22.2% in endemic areas.

Thalassemia

Thalassemia is an inherited autosomal recessive blood disease. In thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin. This can cause the formation of abnormal hemoglobin molecules, thus causing anemia. The term Thalassemia comes from Greek thalassa, meaning "sea" and New Latin -emia, meaning "blood". The etymology indicates the epidemiology of the disorder in that it is commonly seen in patients of Mediterranean descent.

Thalassemia Pathophysiology

In thalassemias, production of the globin chain is affected, while in thalassemia production of the globin chain is affected. globin chains are encoded by two closely linked genes on chromosome 16. globin chains are encoded by a single gene on chromosome 11.

Thalassemia thalassemia

The thalassemias involve the genes HBA1and HBA2, inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome. The loss of one gene diminishes the production of the alpha protein only slightly. A person with this condition is called a "silent carrier" because of the difficulty in detection. This condition is so close to normal. The loss of two genes (two-gene deletion alpha thalassemia) produces a condition with small red blood cells, and at most a mild anemia. People with this condition look and feel normal.

Thalassemia thalassemia

The loss of three alpha genes produces a serious hematological problem (three-gene deletion alpha thalassemia). Patients with this condition have a severe anemia, and often require blood transfusions to survive. The loss of all four alpha genes produces a condition that is incompatible with life. Most people with fourgene deletion alpha thalassemia die in utero or shortly after birth.

Thalassemia thalassemia
Alpha thalassemia has four manifestations, that correlate with the number of defective genes: Silent Carrier State (1 affected gene). This is the one-gene deletion alpha thalassemia condition. The silent carrier will have normal hemoglobin levels and red cell indices but can pass on the affected gene to their offspring. People with this condition are hematologically normal. The only way to diagnose this condition is by DNA analysis.

Thalassemia thalassemia

Alpha Thalassemia Trait (2 affected genes). These patients have lost two alpha globin genes. They have small red cells and a mild anemia. These people are usually asymptomatic. Often, physicians mistakenly diagnose people with mild alpha-thalassemia as having iron deficiency anemia. Iron therapy, of course, does not correct the anemia. Hemoglobin H Disease (3 affected genes). These patients have lost three alpha globin genes. The result is a severe anemia, with small, misshapen red cells and red cell fragments. These patients

Thalassemia thalassemia
With this condition, the large decrease in the amount of alpha globin chains produced causes an excess of beta chains, which then aggregate into beta tetramers (groups of 4 beta chains), known as Hemoglobin H. Hemoglobin H disease is found most often in individuals of Southeast Asian or Mediterranean descent. Alpha Thalassemia Major (also called hydrops fetalis, 4 affected genes). This is the most severe form of alpha thalassemia. I n this condition, no alpha globin is produced, therefore, no Hb A or Hb F are produced.

Thalassemia thalassemia

is due to mutations in one or both of the beta globin genes. There are 100 to 200 mutations that have been identified, but only about 20 are common. beta thalassemia rarely arises from the complete loss of a beta globin gene. The beta globin gene is present, but produces little beta globin protein. In some cases, the affected gene makes essentially no beta globin protein (beta-0-thalassemia). In other cases, the production of beta chain protein is lower than normal, but not zero (beta-(+)thalassemia).

Thalassemia thalassemia

Thalassemia minor, or thalassemia trait: A person with this condition has one normal gene and one with a mutation. These patients are clinically well, and are usually only detected through routine blood testing. Thalassemia Major (also called Cooley's Anemia). Both genes are mutated. This is the most severe form of beta thalassemia. chronic blood transfusions are needed. In some patients the anemia is so severe, that death occurs without transfusions

Thalassemia thalassemia
Thalassemia Intermedia. In this condition, an affected person has two abnormal genes but is still producing some beta globin. Patients with thalassemia intermedia have significant anemia, but are able to survive without blood transfusions. The factors that go into the diagnosis are: 1. The degree to which the patient tolerates the anemia. 2. The threshold of the physician to transfuse patients with thalassemia. The severity of the anemia and health problems experienced depends on the mutations present.

Thalassemia Other Types

Thalassemia can co-exist with other hemoglobinopathies. The most common of these are: hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically similar to thalassemia major or thalassemia intermedia. hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically similar to sickle cell anemia, with the additional feature of splenomegaly hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/o thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/+ thalassemia produces a milder disease.

Thalassemia

Severe anemia with MCV in the 50-60 range (microcytosis) also hypochromic On smear will be target cells and hardly any normal cells

Thalassemia Epidemiology

thalassemias are prevalent in populations that evolved in humid climates where malaria was endemic. It affects all races, as thalassemias protected these people from malaria due to the blood cells' easy degradation. Mediterranean origin, Arabs, and Asians Alpha-thalassemia is prevalent in peoples of Western African and South Asian descent. Beta thalassemia is particularly prevalent among Mediterranean peoples: Greece, Turkey, in particular, Aegean Region such as Izmir, Balikesir, Aydin, Mugla, and Mediterranean Region such as Antalya, Adana, Mersin.

Thalassemia Inheritance

Both and thalassemias are often inherited in an autosomal recessive, although this is not always the case. For the autosomal recessive forms of the disease, both parents must be carriers in order for a child to be affected. If both parents carry a hemoglobinopathy trait, there is a 25% risk with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended