Alpha-thalassemia
Encyclopedia
Alpha-thalassemia is a form of thalassemia
involving the genes HBA1
and HBA2
. Alpha-thalassemia is due to impaired production of 1,2,3, or 4 alpha globin chains, leading to a relative excess of beta globin chains. The degree of impairment is based on which clinical phenotype is present (how many chains are affected).
It can also be acquired, under rare circumstances. Due to the low occurrence of alpha-thalassemia, the disease can be mistaken for iron deficiency anemia.
When noting the genotype, a "-" indicates an absence of function, and a "α" indications a functional alpha chain. (In contrast to the "βo" and "β+" notation used in beta-thalassemia
, in alpha-thalassemia a distinction between absent and reduced function is not usually noted.)
Thalassemia
Thalassemia is an inherited autosomal recessive blood disease that originated in the Mediterranean region. 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...
involving the genes HBA1
HBA1
Hemoglobin, alpha 1, also known as HBA1, is a human gene encoding the hemoglobin protein.-Interactions:Hemoglobin, alpha 1 has been shown to interact with HBB. Interactions between the N-terminal amino groups of the alpha-subunits and the C-terminal histidine of the β-subunits participate in ion...
and HBA2
HBA2
Hemoglobin, alpha 2 also known as HBA2 is a gene that in humans codes for the alpha globin chain of hemoglobin.- Function :The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven alpha like globin genes and pseudogenes: 5'- HBZ - HBZP1 - HBM - HBAP1 - HBA2...
. Alpha-thalassemia is due to impaired production of 1,2,3, or 4 alpha globin chains, leading to a relative excess of beta globin chains. The degree of impairment is based on which clinical phenotype is present (how many chains are affected).
Epidemiology
The worldwide distribution of inherited alpha-thalassemia corresponds to areas of malaria exposure, suggesting a protective role for alpha-thalassemia against the more severe manifestations of malaria. Thus, alpha-thalassemia is common in sub-Saharan Africa, the Mediterranean Basin, the Middle East, South Asia, and Southeast Asia, and different genetic subtypes have variable frequencies in each of these areas. The epidemiology of alpha-thalassemia in the US reflects this global distribution pattern. The most common form of alpha(+) thalassemia seen in the US is due to the -alpha(3.7) deletion, a single alpha-globin gene deletion, and is present in approximately 30% of African Americans. However, even in the homozygous state this disorder will result only in a mild microcytic anemia. The more serious clinical disorders of Hb H and Hb Bart hydrops fetalis syndrome, although found throughout the US today, are more common in the Western US and have dramatically increased in prevalence in the past 2 decades due to increased Asian immigration.Causes
It is most commonly inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome.It can also be acquired, under rare circumstances. Due to the low occurrence of alpha-thalassemia, the disease can be mistaken for iron deficiency anemia.
Pathophysiology
α thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves. The excess γ chains form tetramers which are poor carriers of O2 since their affinity for O2 is too high so it is not dissociated in the periphery. Homozygote α0 thalassaemias, where there is lots of γ4 but no α-globins at all (referred to as Hb Barts), often result in still birth.Types
There are two genetic loci for α globin, and thus four genes in diploid cells. Two genes are maternal in origin and two genes are paternal in origin. The severity of the α thalassemias is correlated with the number of affected α globin genes: the greater, the more severe will be the manifestations of the disease.When noting the genotype, a "-" indicates an absence of function, and a "α" indications a functional alpha chain. (In contrast to the "βo" and "β+" notation used in beta-thalassemia
Beta-thalassemia
Beta-thalassemias are a group of inherited blood disorders caused by reduced or absent synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated...
, in alpha-thalassemia a distinction between absent and reduced function is not usually noted.)
| Alleles affected | Description | Genotype |
|---|---|---|
| One | There is minimal effect. Three α-globin genes are enough to permit normal hemoglobin production, and there are no clinical symptoms. They have been called silent carriers. They may have a slightly reduced mean corpuscular volume Mean corpuscular volume The mean corpuscular volume, or "mean cell volume" , is a measure of the average red blood cell size that is reported as part of a standard complete blood count.... and mean corpuscular hemoglobin Mean corpuscular hemoglobin The mean corpuscular hemoglobin, or "mean cell hemoglobin" , is the average mass of hemoglobin per red blood cell in a sample of blood. It is reported as part of a standard complete blood count... . |
-/α α/α |
| Two | The condition is called alpha thalassemia trait. Two α genes permit nearly normal erythropoiesis Erythropoiesis Erythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin... , but there is a mild microcytic Microcytic anemia Microcytic anemia is a generic term for any type of anemia characterized by small red blood cells. The normal mean corpuscular volume is 76-100 fL, with smaller cells as macrocytic.... hypochromic anemia Anemia Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin... . The disease in this form can be mistaken for iron deficiency anemia Iron deficiency anemia Iron-deficiency anemia is a common anemia that occurs when iron loss occurs, and/or the dietary intake or absorption of iron is insufficient... and treated inappropriately with iron. Alpha thalassemia trait can exist in two forms:
|
-/- α/α or -/α -/α |
| Three | The condition is called Hemoglobin H disease. Two unstable hemoglobins are present in the blood: Hemoglobin Barts (tetrameric γ chains) and Hemoglobin H (tetrameric β chains). Both of these unstable hemoglobins have a higher affinity for oxygen than normal hemoglobin, resulting in poor oxygen delivery to tissues. There is a microcytic Microcytic anemia Microcytic anemia is a generic term for any type of anemia characterized by small red blood cells. The normal mean corpuscular volume is 76-100 fL, with smaller cells as macrocytic.... hypochromic anemia Anemia Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin... with target cell Target cell (codocyte) Codocytes, also known as target cells or Mexican hat cells, are red blood cells that have the appearance of a shooting target with a bullseye... s and Heinz bodies Heinz body Heinz bodies are inclusions within red blood cells composed of denatured hemoglobin.-History:They are named after Robert Heinz , a German physician who in 1890 described these inclusions in connection with cases of hemolytic anemia.-Form and appearance:Heinz bodies appear as small round inclusions... (precipitated HbH) on the peripheral blood smear, as well as splenomegaly Splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any... . The disease may first be noticed in childhood or in early adult life, when the anemia and splenomegaly are noted. |
-/- -/α |
| Four | The fetus Fetus A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The... cannot live once outside the uterus and may not survive gestation: most such infants are dead at birth with hydrops fetalis Hydrops fetalis Hydrops fetalis is a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments. By comparison, hydrops allantois or hydrops amnion are an accumulation of excessive fluid in the allantoic or amniotic space respectively.-Presentation:Locations can... , and those who are born alive die shortly after birth. They are edematous and have little circulating hemoglobin, and the hemoglobin that is present is all tetrameric γ chains (hemoglobin Barts). |
-/- -/- |