Hemoglobinopathy
Hemoglobinopathy is the medical term for a group of blood disorders and diseases that affect red blood cells.
It can be a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. Hemoglobinopathies are inherited single-gene disorders; in most cases, they are inherited as autosomal co-dominant traits. Common hemoglobinopathies include sickle-cell disease. It is estimated that 7% of world's population are carriers, with 60% of total and 70% pathological being in Africa. Hemoglobinopathies are most common in populations from Africa, the Mediterranean basin and Southeast Asia.
Hemoglobinopathies are simply structural abnormalities in the globin proteins themselves. Thalassemias, in contrast, usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. The two conditions may overlap, however, since some conditions which cause abnormalities in globin proteins also affect their production. Thus, some hemoglobinopathies are also thalassemias, but most are not.
Either hemoglobinopathy or thalassemia, or both, may cause anemia. Some well-known hemoglobin variants such as sickle-cell anemia and congenital dyserythropoietic anemia are responsible for diseases, and are considered hemoglobinopathies. However, many hemoglobin variants do not cause pathology or anemia, and thus are often not classed as hemoglobinopathies, because they are not considered pathologies. Hemoglobin variants are a part of the normal embryonic and fetal development, but may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Other variants cause no detectable pathology, and are thus considered non-pathological variants.
Migration patterns
Alkaline electrophoresis
In general on alkaline electrophoresis in order of increasing mobility are hemoglobins A2, E=O=C, G=D=S=Lepore, F, A, K, J, Bart's, N, I, and H.In general a sickling test is performed on abnormal hemoglobins migrating in the S location to see if the red cells precipitate in solution.
Acid electrophoresis
In general on acid electrophoresis in order of increasing mobility are hemoglobins F, A=D=G=E=O=Lepore, S, and C.This is how abnormal hemoglobin variants are isolated and identified using these two methods. For example, a Hgb G-Philadelphia would migrate with S on alkaline electrophoresis and would migrate with A on acid electrophoresis, respectively
use of iso electric focusing to determine quantitative differences in globin chain synthesis and high performance liquid chromatography that separates hemoglobins based on their various affinities for the column
Classification of Hemoglobinopathies
A) Qualitative
Structural abnormalities
Hb variants: Hb structural variants are qualitative defects that cause a change in the structure of the Hb molecule. The majority of Hb variants do not cause disease and are most commonly discovered either incidentally or through newborn screening. A subset of Hb variants can cause severe disease when inherited in the homozygous or compound heterozygous state in combination with another structural variant or a thalassemia mutation. When clinical consequences occur, they may include anemia due to hemolysis or polycythemia due to alterations in the oxygen affinity of the abnormal Hb. Common examples of hemoglobin variants associated with hemolysis include sickle Hb and Hb C. Hb variants can usually be detected by protein-based assay methods; however, DNA-based methods may be required for variants with ambiguous or unusual results from protein analysis.The major functional consequences of Hb structural variants can be classified as follows:
- Change in physical properties : Common beta globin mutations can alter the solubility of the Hb molecule: Hb S polymerizes when deoxygenated and Hb C crystallizes.
- Reduced protein stability : Unstable Hb variants are mutations that cause the Hb molecule to precipitate, spontaneously or upon oxidative stress, resulting in hemolytic anemia. Precipitated, denatured Hb can attach to the inner layer of the plasma membrane of the red blood cell and form Heinz bodies.
- Change in oxygen affinity: High or low oxygen affinity Hb molecules are more likely than normal to adopt the relaxed state or the tense state, respectively. High oxygen affinity variants cause polycythemia. Low oxygen affinity variants can cause cyanosis.
- Oxidation of heme iron: Mutations of the heme binding site, particularly those affecting the conserved proximal or distal histidine residues, can produce M-hemoglobin, in which the iron atom in heme is oxidized from the ferrous state to the ferric state, with resultant methemoglobinemia.
- Sickle cell disease:
- a common hereditary hemoglobinopathy caused by a point mutation in β-globin that promotes the polymerization of deoxygenated hemoglobin, leading to red cell distortion, hemolytic anemia, microvascular obstruction, and ischemic tissue damage.
2. Unstable Hb:
- Methemoglobinemia:
- * a condition caused by elevated levels of methemoglobin in the blood. Methaemoglobin is a form of Hb that contains the ferric form of iron. The affinity for oxygen of ferric iron is impaired. The binding of oxygen to methaemoglobin results in an increased affinity for oxygen in the remaining heme sites that are in ferrous state within the same tetrameric haemoglobin unit.
Amount abnormalities
Copy number variation is also a common genetic cause of Hb disorders, and complex rearrangements and globin gene fusions can also occur.- Thalassemias: Thalassemias are quantitative defects that lead to reduced levels of one type of globin chain, creating an imbalance in the ratio of alpha-like chains to beta-like chains. As noted above, this ratio is normally tightly regulated to prevent excess globin chains of one type from accumulating. The excess chains that fail to incorporate into Hb form non-functional aggregates that precipitate within the RBC. This can lead to premature RBC destruction in the bone marrow and/or in the peripheral blood. Types:
- * Alpha
- * Beta
- * Beta
Hemoglobin variants
- Hb S
- Hb C
- Hb E
- Hb Bart's
- Hb D-Punjab
- Hb O-Arab
- Hb G-Philadelphia
- Hb H
- * Hb Constant Spring
- Hb Hasharon
- Hb Korle-Bu
- Hb Lepore
- Hb M
- Hb Kansas
- Hb J
- Hb N-Baltimore
- Hb Hope
- Hb Pisa
Evolution
Hemoglobin functions:
- Transport of oxygen from the lungs to the tissues: This is due to the peculiar cooperation of the globin chains that allows the molecule to take in more oxygen where there is increased oxygen and to release oxygen in low concentration of oxygen.
- Transport of carbon dioxide from the tissues to the lungs: The end product of tissue metabolism is acidic which increases hydrogen ions in solution. The hydrogen ions combine with bicarbonates to produce water and carbon dioxide. The carbon dioxide is mop up by hemoglobin to favor this reversible reaction.
- Transport of nitric oxide: Nitric oxide is a vasodilatator. This assists in the regulation of vascular reaction in times of stress as experienced during inflammation.
- Anemia due to reduced life span of the red cells of reduced production of the cells e. g. hemoglobin S, C and E.
- Increased oxygen affinity: The red blood cells do not release their oxygen content readily in hypoxic conditions. The bone marow therefore needs to produce more red blood cells and there is polycythemia.
- Unstable hemoglobins: Red blood cells are easily destroyed under stress and hemolysis occurs with possible jaundice.
- Methemoglobinemia: The iron in the heme portion of hemoglobin is easily oxidised and this reduces the ability of hemoglobin to bind oxygen. More deoxygenated hemoglobin are formed and the blood becomes cyanotic.
Hemoglobin Biology
Normal hemoglobins — Human Hbs are tetrameric proteins composed of two pairs of globin chains, each of which contains one alpha-like chain and one beta-like chain. Each globin chain is associated with an iron-containing heme moiety. Throughout life, the synthesis of the alpha-like and the beta-like chains is balanced so that their ratio is relatively constant and there is no excess of either type.The specific alpha and beta-like chains that are incorporated into Hb are highly regulated during development:
- Embryonic Hbs are expressed as early as four to six weeks of embryogenesis and disappear around the eighth week of gestation as they are replaced by fetal Hb.Embryonic Hbs include:
- * Hb Gower-1, composed of two ζ globins and two ε globins
- * Hb Gower-2, composed of two alpha globins and two epsilon globins
- * Hb Portland, composed of two zeta globins and two gamma globins
- Fetal Hb is produced from approximately eight weeks of gestation through birth and constitutes approximately 80 percent of Hb in the full-term neonate. It declines during the first few months of life and, in the normal state, constitutes <1 percent of total Hb by early childhood. Hb F is composed of two alpha globins and two gamma globins.
- Adult Hb is the predominant Hb in children by six months of age and onward; it constitutes 96-97% of total Hb in individuals without a hemoglobinopathy. It is composed of two alpha globins and two beta globins.
- Hb A2 is a minor adult Hb that normally accounts for approximately 2.5-3.5% of total Hb from six months of age onward. It is composed of two alpha globins and two delta globins.