Common Haemoglobin Variants
- Haemoglobin S: This is the main haemoglobin in people with sickle cell disease. Approximately 8% of Britons of West African descent carry the sickle Hb mutation in one of their two beta genes (0.15% of African Americans have sickle cell disease). Those with Hb S disease have two abnormal beta (“βS “or “HbS”) chains and two normal alpha (α) chains. The presence of haemoglobin S causes the red blood cell to deform and assume a sickle shape when exposed to decreased amounts of oxygen (such as might happen with infections or under a general anaesthetic). Sickled red blood cells lead to:
- Haemolysis (premature breakdown of red blood cells) causing low haemoglobin levels (anaemia) and increase in the breakdown product bilirubin (causing yellow skin and eye-whites known as jaundice).
- Blockage of small blood vessels, causing impaired circulation, resulting in strokes, bone pain, chest pain, shortness of breath from micro-clots in the lung, shortening of the fingers, prolonged and painful enlargement of the penis or in children of the spleen. In adults, repeated blockage of blood supply to the spleen usually results in loss of this organ.
A single HbS copy does not cause symptoms unless it is combined with another haemoglobin mutation, such as that causing Hb C (βC).
- Haemoglobin C: About 2-3% of people of West African descent are heterozygotes for haemoglobin C (have one copy of βC). Haemoglobin C disease (seen in homozygotes – those with two copies of βC) is rare and relatively mild. It usually causes a minor amount of haemolytic anaemia and a mild to moderate enlargement of the spleen.
- Haemoglobin E: Haemoglobin E is one of the most common beta chain haemoglobin variants in the world. It is very common in Southeast Asia, especially in Cambodia, Laos, and Thailand.. People who are homozygous for Hb E (have two copies of βE) generally have a mild haemolytic anaemia (a condition where red blood cells break open), microcytic (small cells) red blood cells, and a mild enlargement of the spleen. A single copy of the haemoglobin E gene does not cause symptoms unless it is combined with another mutation, such as the one for beta thalassaemia trait.
Less Common Haemoglobin Variants
There are many other variants. Some are silent – causing no signs or symptoms – while others affect the functionality and/or stability of the haemoglobin molecule. Examples of other variants include: Haemoglobin D, Haemoglobin G, Haemoglobin J, Haemoglobin M, and Haemoglobin Constant Spring, a mutation in the alpha globin gene that results in an abnormally long alpha (α) chain and an unstable haemoglobin molecule. Additional beta chain variant examples are:
- Haemoglobin F: Hb F is the main haemoglobin produced by the fetus, and its role is to transport oxygen efficiently in a low oxygen environment. Production of Hb F stops at birth and decreases to adult levels by 1-2 years of age. Hb F may be increased in several congenital disorders. Levels can be normal or increased in beta thalassaemia and are frequently increased in individuals with sickle cell anaemia and in sickle cell plusbeta thalassaemia. Individuals with sickle cell disease and increased Hb F often have a milder disease, as the F haemoglobin inhibits sickling of the red cells. Hb F levels are also increased in a rare condition called hereditary persistence of fetal haemoglobin (HPFH). This is a group of inherited disorders in which Hb F levels are increased without the signs or clinical features of thalassaemia. Different ethnic groups have different mutations causing HPFH. Hb F can also be increased in some acquired conditions involving impaired red blood cell production. Leukaemias and other myeloproliferative disorders often are also associated with elevated Hb F.
- Haemoglobin H: Hb H is an abnormal haemoglobin that occurs in some cases of alpha thalassaemia. It is composed of four beta (β) globin chains and is produced in response to a severe shortage of alpha (α) chains. Although each of the beta (β) globin chains is normal, the tetramer of 4 beta chains does not function normally. It has an increased affinity for oxygen, holding onto it instead of releasing it to the tissues and cells.
- Haemoglobin Barts: Hb Barts develops in fetuses with alpha thalassaemia. It is formed of four gamma (γ) protein chains when there is severe lack of alpha chains, in a manner similar to the formation of Haemoglobin H. Hb Barts disappears shortly after birth due to dwindling gamma chain production.
A person can also inherit two different abnormal genes, one from each parent. This is known as being compound heterozygous or doubly heterozygous. Several different clinically significant combinations are listed below.
Haemoglobin SC Disease. Inheritance of one beta S gene and one beta C gene results in Haemoglobin SC Disease. These individuals have a mild haemolytic anaemia and moderate enlargement of the spleen. Persons with Hb SC disease may develop the same vaso-occulsive (blood vessel blocking) complications as seen in sickle cell anaemia, (typically bone pain or eye problems) but most cases are less severe.
Sickle Cell – Haemoglobin D Disease. Individuals with sickle cell – Hb D disease have inherited one copy of haemoglobin S and one of haemoglobin D-Los Angeles (or D-Punjab). These patients may have occasional sickle crises and moderate haemolytic anaemia.
Haemoglobin E – beta thalassaemia. Individuals who are doubly heterozygous for haemoglobin E and beta thalassaemia have an anaemia that can vary in severity, from mild (or asymptomatic) to severe.
Haemoglobin S – beta thalassaemia. Sickle cell – beta thalassaemia varies in severity, depending on the beta thalassaemia mutation inherited. The more severe the beta-thalassaemia variant (so the less normal beta chain produced), the more the patient will resemble a homozygous sickle cell disease rather than trait individual. Some mutations result in decreased beta globin production (beta+) while others completely eliminate it (beta0). Sickle cell – beta+ thalassaemia tends to be less severe than sickle cell – beta0 thalassaemia. Patients with sickle cell – beta0 thalassaemia tend to have more irreversibly sickled cells, more frequent vaso-occlusive problems, and more severe anaemia than those with sickle cell – beta+ thalassaemia. It is often difficult to distinguish between sickle cell disease and sickle cell – beta0 thalassaemia.