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. Some subtypes of hereditary elliptocytosis are significantly more prevalent in regions where malaria is endemic. For example, in equatorial Africa its incidence approaches 160 per 10,000, and in Malayan natives its incidence is over 15% (1500-2000 per 10,000). Being an almost wholly autosomal dominant disorder, there is no predilection towards either sex in hereditary elliptocytosis. The most important exception to this rule of autosomal dominant inheritance is for a subtype of hereditary elliptocytosis called hereditary pyropoikilocytosis (HPP). This condition is autosomal recessive.
There are a number of different subtypes of hereditary elliptocytosis. 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. The following categorisation of the disorder demonstrates its heterogeneity (in approximate order from least severe to most severe):
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 protein 4.1 mutations. Spectrin tetramers must bind to actin in order to create a proper cytoskeleton scaffold, and protein 4.1 is an important protein involved in the stabilisation of the link between spectrin and actin. Similarly to the spectrin mutations, protein 4.1 mutations cause a mild haemolytic anaemia in the heterozygous state, and a severe haemolytic disease in the homozygous state. Erythrocytes of individuals who are homozygous for this mutation type show not only a destabilised cytoskeleton but also disorder of molecules within the cell membrane itself, which is evidence that protein 4.1 plays some part in maintaining the normal organisation of the cell membrane.
The third group of mutations which lead to elliptocytosis are those which 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 protein 4.1 to the cell membrane. It is thought that elliptocytosis in glycophorin C deficiency is actually the consequence of a protein 4.1 deficit, as glycophorin C deficient individuals also have reduced intracellular protein 4.1 (probably due to the reduced number of binding sites for protein 4.1 in the absence of glycoprotein C). Plasmodium falciparum (the pathogen responsible for malaria) has a surface protein called erythrocyte-binding antigen 140, which is now known to bind to glycophorin C. This suggests that plasmodium falciparum is less able to bind to the erythrocytes of those with the Leach phenotype, suggesting these individuals have a relative resistance to malaria. Clinically, this has not yet been shown.
Multiplication of mutations tends to infer more serious disease. For instance, in HPP, the most common genotype results from receiving 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 which causes the affected individual's cells to preferentially produce the defective α-spectrin rather than normal α-spectrin.
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.
Folate helps to reduce the extent of haemolysis in those with significant haemolysis due to hereditary elliptocytosis.
Because the spleen is the bodily organ which 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.