Congenital dyserythropoietic anemia type II
Description, Causes and Risk Factors:
Abbreviation: CDA II.
Congenital dyserythropoietic anemia type II (CDA II) is the most frequent type of congenital dyserythropoietic anemia. More than 200 cases have been described in the literature. CDA II is also inherited as an autosomal recessive disorder, but the gene or genes responsible have not yet been identified. Linkage analysis identified a putative locus on chromosome 20 in the families from southern Italy, but there is likely to be genetic heterogeneity.
The underlying defect in Congenital dyserythropoietic anemia type II is a failure of normal glycosylation of membrane proteins, particular band 3, the anion channel of the red cell. Polyacrylamide gel electrophoresis (PAGE) has shown the band 3 protein from CDA II red cells migrates faster than normal, the reduction in molecular weight being the result of loss of glycosyl residue rather than an abnormal protein. In Congenital dyserythropoietic anemia type II there is a clustering of band 3 compared with the normal even distribution of the fully glycosylated protein. Other membranes proteins including band 4, 5, and some plasma proteins, such as transferring, are also underglycoslated. The primary molecular defect in CDA II is unknown. There is no linkage with genes encoding common glycosylation enzymes. Heterozygotes may also show evidence of abnormal glycosylation.
Congenital dyserythropoietic anemia type II (CDA II) is caused by mutations in the SEC23B gene (Cytogenetic Location: 20p11.23). The SEC23B gene provides instructions for making one component of a large group of interacting proteins called coat protein complex II (COPII). COPII is involved in the formation of vesicles, which are small sac-like structures that transport proteins and other materials within cells. Specifically, COPII triggers the formation of vesicles in a cellular structure called the endoplasmic reticulum (ER), which is involved in protein processing and transport. These COPII vesicles carry proteins that are destined to be exported out of cells (secreted).
The SEC23B protein is very similar to the protein produced from a related gene, SEC23A. These proteins are both components of COPII, and they appear to have overlapping functions. In most types of cells, if one of these proteins is missing, the other may be able to compensate for the loss. However, research indicates that the SEC23B protein may have a unique function in developing red blood cells (erythroblasts).
At least 20 mutations in the SEC23B gene have been identified in people with congenital dyserythropoietic anemia (CDA) type II. Most of these mutations change single protein building blocks (amino acids) in the SEC23B protein. Other mutations delete genetic material from the SEC23B gene or alter the way the gene's instructions are used to make the SEC23B protein. The mutations responsible for CDA type II likely disrupt the function of the SEC23B protein. However, researchers suspect that these mutations do not completely eliminate the function of the protein, which appears to be essential for life.
It is unclear how SEC23B mutations cause the characteristic features of Congenital dyserythropoietic anemia type II. The abnormal SEC23B protein leads to the production of erythroblasts that are unusually shaped and may have extra nuclei. These defective erythroblasts cannot develop into functional mature red blood cells. The resulting shortage of healthy red blood cells leads to the characteristic signs and symptoms of anemia, as well as complications including an enlarged liver and spleen (hepatosplenomegaly) and an abnormal buildup of iron that can damage the body's organs.
A study led by the ENERCA member analyzes two mutations (E109K and R14W) of the SEC23B gene and discovers one of them is responsible for the higher frequency of CDA II in Italian population. The first mutation, E109K, may have originated in the Middle East about 2,400 years ago and may have spread in the heyday of the Roman Empire. The other one may have originated in Southern Italy about 3.000 years ago.
As many other kinds of anemia, Congenital dyserythropoietic anemia type II is characterized by ineffective erythropoiesis. It leads patients to a decrease in the number of produced reticulocytes and a low concentration of hemoglobin in the blood. This shortage prevents the blood from carrying an adequate supply of oxygen to the body's tissues, resulting in various symptoms of anemia including: tiredness (fatigue), weakness, pale skin, and other similar complications. It was first described in 1968, and soon became clear that the condition was heterogeneous, and three forms became well known, with type II being the most frequent
There are characteristics morphologic features of Congenital dyserythropoietic anemia type II on bone marrow aspirate. There is erythroid hyperplasia with binuclearity or multinuclearity affecting intermediate and late erythroblast, the nuclei being equal in size and DNA content, Pseudo-Gaucher macrophages may be observed.
In clinical practice, evidence of any type of congenital dyserythropoietic anemias is primarily based on the morphology of peripheral blood and bone marrow, although confirmation of the diagnosis of the two most frequent types CDA I and CDA II is based on more refined tests. These tests are expensive and available in only a few specialized laboratories. The correct diagnosis of congenital anemias is often delayed. Many hematologists or clinical pathologists have never seen a case of CDA and do not recognize the well known morphological abnormalities or because, by misinterpretation of clinical and laboratory findings, a bone marrow biopsy is not performed. On the other hand, the diagnosis of a congenital dyserythropoietic anemia is often erroneously suspected, since the observer overvalues the presence of abnormalities that can be seen in the CDAs but also in other more common red cell disorders.
In Congenital dyserythropoietic anemia type II, the most specific finding is the presence of binucleated cells with equal size of two nuclei. The fraction of such binucleated cells is usually more than 10% of all erythroid precursors. If the fraction of binucleated erythroblasts is related to the compartment of late polychromatic and mature oxyphilic erythroblasts, the 95% confidence interval is 13-16%. No more than 2% of binucleated cells may be found in normal individuals or a variety of red cell disorders with erythroid hyperplasia. If more than 10% of typical binucleated erythroblasts are seen, together with more than 2% of cells with karyorrhexis, the diagnosis of CDA II is almost confirmed, and confirmatory tests such as sequencing the SEC23B gene are indicated.
- The MCV is normal or slightly increased.
- The reticulocyte count is usually or may be modestly raised.
- The blood film usually shows red cells anisocytosis, acanthocytes and basophilic stippling, and there may be occasional circulating binucleate normoblast.
- Unconjugated bilirubin is raised and serum haptoglobin levels are low or undetectable.
- Impaired liver function tests may be secondary to cholelithiasis, or to hepatic iron loading.
- Serum ferritin levels increase with age, although with considerable individual variation.
The management of Congenital dyserythropoietic anemia type II depends upon the severity of the anemia and the degree of iron overload. In many cases, no particular treatment is requested. Treatment should be implemented, if in severe cases regular transfusions are needed, or if the physical ability and quality of life is impaired. Until now, no medications have proven its efficiency. The only possibility to improve the situation is the removal of an enlarged spleen in severe cases. However, since the spleen has relevant functions for the immunity, the decision whether this operation is of benefit should be made by the pediatrician or internist with special experience in the field. He of she will take measures to minimize the risk of a severe bacterial infection, and all patients without a functional spleen should be aware of the risks and carry a medical alert card to inform the physicians about the risk of infections which need immediate antibiotic treatment. However, splenectomy does not modulate the ineffective erythropoiesis of Congenital dyserythropoietic anemia type II, and consequently does not prevent iron loading. The major indication for splenectomy is therefore to prevent transfusion dependence in severely anemic patients. Splenectomy has also been used to increase the hematocrit to a level that allows regular phlebotomy to facilitate the management of iron overload.
Ferritin should be monitored regularly and iron chelation therapy and phlebotomy should be initiated in patients who demonstrate increasing ferritin levels.
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.