Hereditary elliptocytosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Niyousha Danesh M.D., M.P.H.

Hereditary elliptocytosis is one of the most common red blood cell membrane disorder in which a large proportion of the erythrocytes (i.e. red blood cells) are elliptical rather than biconcave disc-shaped and it shortens RBC survival. It is also known as ovalocytosis. The main disorder in Hereditary elliptocytosis is cytoskeletal proteins defect,which influence the biconcave appearance of RBCs. patients with HE are usually asymptomatic however they present sometime hemolysis and haemolytic anaemia.^[1]

RBC anomaly in Hereditary elliptocytosis was first observed in 1860 by Goltz, ^[2]and Elliptocytosis, elliptical shape of RBCs was described in 1904 by Dresbach. ^[3] Bishop recognized the familial inheritance as autosomal dominant of HE in 1914 and Hunter and Adams affirmed it’s hereditary condition in 1929.^[2] Recent studies demonstrate that, the severity of symptoms in patients with Hereditary elliptocytosis is variable and it can be related to genetic variations.^[4]

Hereditary elliptocytosis is commonly an autosomal dominant (AD) disorder, in which mutations in alpha-spectrin or beta-spectrin occur, that leads to quantity or structural defects of the cytoskeletal proteins in RBCs. Other cytoskeletal proteins such as glycophorin and band 4.1 can also be mutated in this disease.^[5]

Another form of inheritance in HE is autosomal recessive (AR) ,it is called hereditary pyropoikilocytosis (HPP), and rarely spontaneous mutations have been reported.^[1]

Quality and quantity defects of the cytoskeletal proteins are responsible in Hereditary elliptocytosis. These cytoskeletal proteins are necessary for maintenance of RBCs structure, specially their biconcave morphology.In this disease the protein scaffolding in the inner side of RBC is influenced and results in defective RBCs membrane

Hereditary elliptocytosis is commonly inherited as autosomal dominant. The only exception is autosomal recessive inheritance of hereditary pyropoikilocytosis (HPP). The spontaneous mutations occurs rarely.

The RBC membrane consists of a lipid bilayer and a protein cytoskeleton, which increase RBC resistance, Spectrin is one of the main part of this scaffold and has 2 chains, alpha and beta. Separate genes encode alpha and beta chains and after being twisted together, they create an elongated heterodimer. These heterodimers  build tetramers in the head part and they are linked to other cytoskeletal proteins at the tail regien,protein 4.1 and actin. Then protein 4.1 and actin bind to glycophorin A, band 3, and glycophorin C, the transmembrane proteins, connecting the scaffold to the lipid bilayer.

Mutations involved in the pathogenesis of HE can occur in each one of the cytoskeletal proteins,such as spectrins, band 4.1 or glycophorin C.

These mutations affect mainly alpha- and beta-spectrin,impairing of the spectrin heterodimer formation. The combination of  heterodimer and the lipid anchoring complex can also be influenced.

Normal erythrocytes remain in the blood circulation for 120 days and they can maintain their elastic recoil and their discoid shape after passing through the capillaries in microcirculation , yet the elliptical shape of RBCs reduces the elasticity of RBCs, so their discoid shape is damaged and their ability to pass through 2 micron capillaries is reduced, so they are  trapped and removed by the spleen. The reduction in surface to volume ratio of RBCs and their premature destruction leads to extravascular hemolysis and the clinical signs and symptoms of these disease.^[6][7]

Hereditary elliptocytosis is one of the most common RBC membrane disorders worldwide,and the incidence of HE is 25-50 per 100,000 individuals.

The prevalence of Hereditary elliptocytosis is 50 out of 100,000 affected cases in Northern European countries and North America.^[1]

In endemic areas for malaria,the incidence of HE is notably higher, this incidence ranges from a low of 600 per 100,000 persons in equatorial Africa to a high of 30,000 per 100,000 persons in Malayan aborigines.

This large number of prevalence is because of relative resistance of elliptocytes against malaria in the endemic areas.

As many patients with HE are asymptomatic, the true incidence is not known.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Niyousha Danesh M.D., M.P.H

RBC anomaly in Hereditary elliptocytosis was first observed in 1860 by Goltz,^[1]

and Elliptocytosis, elliptical shape of RBCs was described in 1904 by Dresbach.^[2]Bishop recognized the familial inheritance as autosomal dominant of HE in 1914 and Hunter and Adams affirmed it’s hereditary condition in 1929. ^[1] Recent studies demonstrate that, the severity of symptoms in patients with Hereditary elliptocytosis is variable and it can be related to genetic variations. ^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Niyousha Danesh M.D., M.P.H

The most common type of elliptocytosis is Common hereditary elliptocytosis and it has been more than other types investigated. Common hereditary elliptocytosis has a great variety in the clinical symptoms and severity. 5-10% of patients with this form of elliptocytosis manifest clinically significant haemolytic anaemia , whereas other subtypes of this disease present more sever symptoms.

The classification of hereditary elliptocytosis types and it’s heterogeneity is demonstrated below ,it is organized from the least severe to the most severe.^[1]:

• Common hereditary elliptocytosis
  • asymptomatic carriers : the individual presenting no symptoms of disease and this subtype is only diagnosed via peripheral blood smear.
  • Mild disease – the individual has a mild and compensated haemolytic anaemia but manifests no symptoms.
  • Sporadic haemolysis – the individual has a predilection towards haemolysis in the presence of particular comorbidities, including infections, and [[Cyanocobalamin|vitamin BTemplate:Ssub]] 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 lie anywhere in the spectrum between having a mild haemolytic anaemia and having a life-threatening haemolytic anaemia with symptoms mimicking those of HPP (see below)
  • 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 simultaneously 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 or Filipino, has a mild haemolytic anaemia, and has resistance to malaria ^[2]
• Southeast Asian ovalocytosis and spherocytic elliptocytosis are less common subtypes predominantly affecting those of south-east Asian and European ethnic groups, respectively.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Niyousha Danesh M.D., M.P.H

Hereditary elliptocytosis (HE) includes inherited a spectrum of red blood cell (RBC) disorders, that present heterogeneity in clinical symptoms, biochemistry and genetics. All of the Hereditary elliptocytosis subtypes have the elliptical morphologic shape RBCs in common, which leads to reduced RBC survival.^[1]

Quality and quantity defects of the cytoskeletal proteins are responsible in Hereditary elliptocytosis. These cytoskeletal proteins are necessary for maintenance of RBCs structure, specially their biconcave morphology.^[2]

Hereditary elliptocytosis is commonly inherited as autosomal dominant. The only exception is autosomal recessive inheritance of hereditary pyropoikilocytosis (HPP). The spontaneous mutations occurs rarely. ^[3]

As we mentioned hereditary elliptocytosis is caused by cytoskeletal proteins defects. In this disease the protein scaffolding in the inner side of RBC is influenced and results in defective RBCs membrane

The RBC membrane consists of a lipid bilayer and a protein cytoskeleton, which increase RBC resistance, Spectrin is one of the main part of this scaffold and has 2 chains, alpha and beta. Separate genes encode alpha and beta chains and after being twisted together, they create an elongated heterodimer. These heterodimers  build tetramers in the head part and they are linked to other cytoskeletal proteins at the tail regien,protein 4.1 and actin. Then protein 4.1 and actin bind to glycophorin A, band 3, and glycophorin C, the transmembrane proteins, connecting the scaffold to the lipid bilayer.

Mutations involved in the pathogenesis of HE can occur in each one of the cytoskeletal proteins,such as spectrins, band 4.1 or glycophorin C. ^[4]

These mutations affect mainly alpha- and beta-spectrin,impairing of the spectrin heterodimer formation. The combination of  heterodimer and the lipid anchoring complex can also be influenced.

Some mutations alter the quantity of glycophorin C, namely Leach phenotype.

Various point mutations have been reported in some families, which present clinical variation of HE.

Normal erythrocytes are 7 microns, biconcave and have central pallor. They remain in the blood circulation for 120 days and they can maintain their elastic recoil  and their discoid shape after passing through the capillaries in microcirculation , yet the elliptical shape of RBCs reduces the elasticity of RBCs, so their discoid shape is damaged and their ability to pass through 2 micron capillaries is reduced, so they are  trapped and removed by the spleen. The reduction in surface to volume ratio of RBCs and their premature destruction leads to extravascular hemolysis and the clinical signs and symptoms of these disease.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Niyousha Danesh M.D., M.P.H

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.Some subtypes of hereditary elliptocytosis are significantly more prevalent in regions where malaria is endemic.

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.

• 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.^[1]

• It is estimated that its incidence is between 3 and 5 per 10,000 in the USA.^[2]

• 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).^[3]

• 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. ^[4]

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According to the United States Preventive Services Task Force, screening for Hereditary elliptocytosis is not recommended.

According to the United States Preventive Services Task Force, screening for Hereditary elliptocytosis is not recommended.

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Those with hereditary elliptocytosis have a good prognosis, only those with very severe disease have a shortened life expectancy.

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