Hereditary elliptocytosis

Hereditary elliptocytosis is a blood disorder in which a large proportion of the sufferer's erythrocytes (i.e. red blood cells) are elliptical rather than bi-concave disc-shaped. It is also known as ovalocytosis. The disorder predisposes to haemolytic anaemia

Historical perspective

Elliptocytosis was first described in 1904, and was first recognised as a hereditary condition in 1932. More recently it has become clear that there is much genetic heterogeneity amongst sufferers, and the severity of the condition is highly variable.

Aetiology

The incidence of hereditary elliptocytosis is hard 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. Interestingly, some subtypes of hereditary elliptocytosis are significantly more prevalant 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 30% (3000 per 10,000). Being an almost wholly autosomal dominant disorder, there is no prediliction 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):

Common hereditary elliptocytosis
- With asymptomatic carrier status - the individual has no symptoms of disease and diagnosis is only able to be made on blood film
- With mild disease - the individual has no symptoms and a mild and compensated haemolytic anaemia
- With sporadic haemolysis - the individual has a prediliction towards haemolysis in the presence of particular comorbidities, including infections, and vitamin B deficiency
- With neonatal poikilocytosis - during the first year of life only the individual has a symptomatic haemolytic anaemia with poikilocytosis
- With chronic haemolysis - the individual has a moderate to severe symptomatic haemolytic anaemia (this subtype has variable penetrance in some pedigrees)
- With homozygosity or compound heterozygosity - depending on the exact mutations involved, the individual may have a mild to life-threatening haemolytic anaemia with symptoms mimicking those of HPP
- With pyropoikilocytosis (HPP) - ''the individual is typically of African descent and has a life-threateningly severe haemolytic anaemia with micropoikilocytosis (small and misshapen erythrocytes) that is compounded by a marked instability of erythrocytes in even mildly elevated temperatures (pyropoikilocytosis is often found in burns victims and is the term is commonly used in reference to such people)
Spherocytic elliptocytosis (also called hereditary haemolytic ovalocytosis) - the individual is typically of European descent and both elliptocytes and spherocytes are simulaneously present in their blood
South-east Asian ovalocytosis (SAO) (also called stomatocytic elliptocytosis) - the individual is of South-East Asian descent (typically Malaysian, Indonesian, Melanesian, New Guinean and Filipino, has a mild haemolytic anaemia, and has resistance to malaria

Pathophysiology

Common hereditary elliptocytosis

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). Interestingly, 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.

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.

Spherocytic elliptocytosis

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. Except for protein 4.2 linked disease (which is autosomal recessive), spherocytic elliptocytosis is an autosomal dominant condition.

Southeast Asian ovalocytosis

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 band 3, which lies in the cell membrane itself. Band 3 normally binds to another membrane-bound protein called ankyrin, but in SAO this bond is stronger than normal. Other abnormalities include tighter tethering of band 3 to the cell membrane, increased tyrosine phosphorylation of band 3, and reduced sulfate anion transport through the cell membrane. These (and possibly other) consequences of the SAO mutations lead to the following erythrocyte abnormalities:

a greater robustness of cells, including
- a reduction in cellular sensitivity to osmotic pressures
- a reduction in fragility related to temperature change
- greater rigidity of cell membranes
- loss of sensitivity to substances which cause spiculation of cells
a reduction in expression of multiple antigens

References

Liu S, Palek J, Yi SJ, Nichols PE, Derick LH, Chiou S, Amato D, Corbett JD, Cho MR and Golan DE. Molecular Basis of Altered Red Blood Cell Membrane Properties in Southeast Asian Ovalocytosis: Role of the Mutant Band 3 Protein in Band 3 Oligomerization and Retention by the Membrane Skeleton. Blood 1995;86:349-58. PMID 7795244.

Genetic disorders | Hematology