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Blood smear showing elliptocytes
Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the sufferer's erythrocytes (i.e. red blood cells) are elliptical rather than the typical biconcave disc shape. It is one of many red-cell membrane defects. In its severe forms, this disorder predisposes to haemolytic anaemia.
Elliptocytosis was first described in 1904, and was first recognised as a hereditary condition in 1932. More recently it has become clear that the severity of the condition is highly variable, and there is much genetic variability amongst those affected.
The incidence of hereditary elliptocytosis is hard to determine, as many sufferers of the milder forms of the disorder are asymptomatic and their condition never comes to medical attention. Around 90% of those with this disorder are thought to fall into the asymptomatic population. It is estimated that its incidence is between 3 and 5 per 10,000 in the USA, and that those of African and Mediterranean descent are of higher risk. Because it can confer resistance to malaria, some subtypes of hereditary elliptocytosis are significantly more prevalent in regions where malaria is endemic. For example, in equatorial Africa its incidence is estimated at 60-160 per 10,000, and in Malayan natives its incidence is 1500-2000 per 10,000. Almost all forms of hereditary elliptocytosis are autosomal dominant disorder, and both sexes are therefore at equal risk of having the condition. The most important exception to this rule of autosomal dominance is for a subtype of hereditary elliptocytosis called hereditary pyropoikilocytosis (HPP), which is autosomal recessive.
There are three major forms of hereditary elliptocytosis: common hereditary elliptocytosis, spherocytic elliptocytosis and southeast Asian ovalocytosis.
Common hereditary elliptocytosis is the most common form of elliptocytosis, and the form most extensively researched. Even when looking only at this form of elliptocytosis, there is a large variation in its severity. A clinically significant haemolytic anaemia occurs only in 5-10% of sufferers, with a strong bias towards those with more severe subtypes of the disorder.
Southeast Asian ovalocytosis and spherocytic elliptocytosis are less common subtypes predominantly affecting those of south-east Asian and European ethnic groups, respectively.
The following categorisation of the disorder demonstrates its heterogeneity (in approximate order from least severe to most severe):
A number of genes have been linked to common hereditary elliptocytosis. These mutations have a common end result; they destabilise the cytoskeletal scaffold of cells. This stability is especially important in erythrocytes as they are constantly under the influence of deforming shear forces. As disc-shaped erythrocytes pass through capillaries, which can be 2-3 micrometres wide, they are forced to assume an elliptical shape in order to fit through. Normally, this deformation lasts only as long as a cell is present in a capillary, but in hereditary elliptocytosis the instability of the cytoskeleton means that erythrocytes deformed by passing through a capillary are forever rendered elliptical. These elliptical cells are taken up by the spleen and removed from circulation when they are younger than they would normally be, meaning that the erythrocytes of people with hereditary elliptocytosis have a shorter than average life-span (a normal person's erythrocytes average 120 days or more).
The most common genetic defects (present in two-thirds of all cases of hereditary elliptocytosis) are in genes for the polypeptides α-spectrin or β-spectrin. These two polypeptides combine with one another in vivo to form an αβ heterodimer. These αβ heterodimers then combine together to form spectrin tetramers. These spectrin tetramers are among the basic structural subunits of the cytoskeleton of all cells in the body. Although there is much interindividual variability, it is generally true that 'α'-spectrin mutations result in an inability of α-spectrin to interact properly with β-spectrin to form a heterodimer. In contrast, it is generally true that 'β'-spectrin mutations lead to αβ heterodimers being incapable of combining to form spectrin tetramers. The end result is a weakness in the cytoskeleton of the cell. Individuals with a single mutation in one of the spectrin genes are usually asymptomatic, but those who are homozygotes or are compound heterozygotes (i.e. they are heterozygous for two different elliptocytosis-causing mutations) have sufficient cell membrane instability to have a clinically significant haemolytic anaemia.
Less common than spectrin mutations are band 4.1 mutations. Spectrin tetramers must bind to actin in order to create a proper cytoskeleton scaffold, and band 4.1 is an important protein involved in the stabilisation of the link between spectrin and actin. Similarly to the spectrin mutations, band 4.1 mutations cause a mild haemolytic anaemia in the heterozygous state, and a severe haemolytic disease in the homozygous state.
The third group of mutations that lead to elliptocytosis are those that cause glycophorin C deficiencies. There are three phenotypes caused by abnormal glycophorin C, these are named Gerbich, Yus and Leach (see glycophorin C for more information). Only the rarest of the three, the Leach phenotype, causes elliptocytosis. Glycophorin C has the function of holding band 4.1 to the cell membrane. It is thought that elliptocytosis in glycophorin C deficiency is actually the consequence of a band 4.1 deficit, as glycophorin C deficient individuals also have reduced intracellular band 4.1 (probably due to the reduced number of binding sites for band 4.1 in the absence of glycoprotein C).
Inheritance of multiple mutations tends to infer more serious disease. For instance, the most common genotype responsible for HPP occurs when the affected individual inherits an α-spectrin mutation from one parent (i.e. one parent has hereditary elliptocytosis) and the other parent passes on an as-yet-undefined defect that causes the affected individual's cells to preferentially produce the defective α-spectrin rather than normal α-spectrin.
The molecular defect associated with spherocytic elliptocytosis has yet to be elucidated. As with common hereditary elliptocytosis, multiple gene defects are probably capable of causing this phenotype. Mutations in the genes coding for β-spectrin, glycophorin C and protein 4.2 have all been implicated in spherocytic elliptocytosis.
One suggestion is that spherocytic elliptocytosis is a hybrid phenotype that is the result of two different mutations, one that would normally cause mild common hereditary elliptocytosis and another mutation that would cause mild hereditary spherocytosis (a different red-cell membrane defect).
The primary defect in SAO differs significantly from other forms of elliptocytosis in that it is a defect in the gene coding for a protein that is not directly involved in the cytoskeleton scaffolding of the cell. Rather, the defect lies in a protein known as the band 3 protein, which lies in the cell membrane itself. The band 3 protein normally binds to another membrane-bound protein called ankyrin, but in SAO this bond is stronger than normal. Other abnormalities include tighter tethering of the band 3 protein to the cell membrane, increased tyrosine phosphorylation of the band 3 protein, reduced sulfate anion transport through the cell membrane, and more rapid ATP consumption. These (and probably other) consequences of the SAO mutations lead to the following erythrocyte abnormalities:
These changes are thought to give rise to the scientifically and clinically interesting phenomenon that those with SAO exhibit - a marked in vivo resistance to infection by the causative pathogen of malaria, Plasmodium falciparum. Unlike those with the Leach phenotype of common hereditary elliptocytosis (see above), there is a clinically significant reduction in both disease severity and prevalence of malaria in those with SAO. Because of this, the 35% incidence rate of SAO along the north coast of Madang Province in Papua New Guinea, where malaria in endemic, is a good example of natural selection.
The reasons behind the resistance to malaria become clear when given an explanation the way in which Plasmodium falciparum invades its host. This parasite is an obligate intracellular parasite, which must enter the cells of the host it is invading. The band 3 proteins aggregate on the cell membrane at the site of entry, forming a circular orifice that the parasite squeezes through. These band 3 proteins act as receptors for the parasite. Normally a process much like endocytosis occurs, and the parasite is able to isolate itself from the intracellular proteins that are toxic to it while still being inside an erythrocyte (see figure 2). The increased rigidity of the erythrocyte membrane in SAO is thought to reduce the capacity of the band 3 proteins to cluster together, thereby making it more difficult for the malaria parasite to properly attaching to and enter the cell. The reduced free ATP within the cell has been postulated as a further mechanism behind which SAO creates a hostile environment for Plasmodium falciparum.
The vast majority of those with hereditary elliptocytosis require no treatment whatsoever. They have a mildly increased risk of developing gallstones, which is treated surgically with a cholecystectomy if pain becomes problematic.
Folate helps to reduce the extent of haemolysis in those with significant haemolysis due to hereditary elliptocytosis.
Because the spleen breaks down old and worn-out blood cells, those individuals with more severe forms of hereditary elliptocytosis can have a splenomegaly, which causes a worsening of the signs and symptoms of their anaemia. These can include:
Removal of the spleen (splenectomy) is effective in reducing the severity of these complications, but is associated with an increased risk of overwhelming bacterial septicaemia, and is only performed on those with significant complications. Because many neonates with severe elliptocytosis progress to have only a mild disease, and because this age group is particularly susceptible to pneumococcal infections, a splenectomy is only performed on those under 5 years old when it is absolutely necessary.
Because chronic haemolysis increases an individual's risk of gallstones, people with elliptocytosis have an increased risk of suffering from gallstones. This risk is relative to the severity of the disease, and those with symptomatic elliptocytosis should have regular abdominal ultrasounds to monitor the progression of their gall bladder disease.