Congenital dyserythropoietic anemia type 2 (CDA II) is an inherited blood disorder characterized by mild to severe anemia. It is usually diagnosed in adolescence or early adulthood. Many affected individuals have yellowing of the skin and eyes (jaundice) and an enlarged liver and spleen (hepatosplenomegaly) and gallstones. This condition also causes the body to absorb too much iron, which builds up and can damage tissues and organs. In particular, iron overload can lead to an abnormal heart rhythm (arrhythmia), congestive heart failure, diabetes, and chronic liver disease (cirrhosis). Rarely, people with CDA type II have mediastinal tumors. CDA type II usually results from mutations in the SEC23B gene. It is inherited in an autosomal recessive pattern. Treatment depends on the severity of the symptoms and may involve blood transfusions, iron chelation therapy and removal of the spleen and gallbladder.

CDA type I usually results from mutations in the CDAN1 gene. Little is known about the function of this gene, and it is unclear how mutations cause the characteristic features of CDA type I. Some people with this condition do not have identified mutations in the CDAN1 gene, leading researchers to believe that mutations in at least one other gene can also cause this form of the disorder.

CDA type II is caused by mutations in the SEC23B gene. This gene provides instructions for making a protein that is involved in the transport of other proteins within cells. During the development of red blood cells, this protein may help ensure that proteins are transported to the areas where they are needed. Researchers are working to determine how mutations in the SEC23B gene lead to the signs and symptoms of CDA type II.

The genetic cause of CDA type III has not been identified. It likely results from mutations in a gene located on the long arm of chromosome 15 at a position designated 15q22. Researchers continue to search for the specific gene associated with this form of the condition.

The genetic changes responsible for CDA disrupt the normal development of red blood cells, a process called erythropoiesis. The term "dyserythropoietic" in the name of this condition means abnormal red blood cell formation. In people with CDA, immature red blood cells called erythroblasts are unusually shaped and have other abnormalities (such as extra nuclei). These abnormal 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 hepatosplenomegaly and an abnormal buildup of iron.

Normal Function

The CDAN1 gene provides instructions for making a protein called codanin-1. Although this protein is active in cells throughout the body, very little is known about its function.

A recent study suggests that codanin-1 is associated with a form of DNA called heterochromatin. Heterochromatin is densely packed DNA that contains few functional genes, but it plays an important role in maintaining the structure of the nucleus (where most of the cell's DNA is located).

Researchers speculate that codanin-1 may be involved in the formation of red blood cells, a process called erythropoiesis. Specifically, this protein may play a key role in the organization of heterochromatin during the division of these developing cells.

Health Conditions Related to Genetic Changes

Congenital dyserythropoietic anemia

More than 30 mutations in the CDAN1 gene have been identified in people with congenital dyserythropoietic anemia (CDA) type I. Most of these mutations change single protein building blocks (amino acids) in the codanin-1 protein. The CDAN1 mutations that cause CDA type I likely reduce the function of codanin-1. 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 CDAN1 mutations cause the characteristic features of CDA type I. A shortage of functional codanin-1 somehow disrupts the normal development of red blood cells. In people with CDA type I, immature red blood cells called erythroblasts are large, unusually shaped, and have an abnormally formed nucleus. 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.

Other Names for This Gene

• CDA-I
• CDA1
• CDAI
• CDAN1_HUMAN
• codanin
• congenital dyserythropoietic anemia, type I
• DLT
• PRO1295

Genomic Location

Normal Function

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).

Health Conditions Related to Genetic Changes

Congenital dyserythropoietic anemia

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 CDA 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.

Cowden syndrome

MedlinePlus Genetics provides information about Cowden syndrome

Other Names for This Gene

• CDA-II
• CDAII
• HEMPAS
• SC23B_HUMAN
• Sec23 homolog B
• Sec23 homolog B (S. cerevisiae)
• Sec23 homolog B, COPII coat complex component
• SEC23-like protein B
• SEC23-related protein B
• transport protein SEC23B

Genomic Location

The goal of CDA type 2 treatment is to address and prevent complications from anemia and iron overload. Most people with CDA type 2 developiron overload, for some this is as early as in their 20's. If a person with CDA type 2 has mild anemia, but evidence of iron loading, treatment may involve phlebotomy. An alternative treatment is chelation therapy. In particular, chelation therapy is preferred for people with iron (ferritin) levels greater than 1000 mg/L.

Many people with CDA-2 maintain hemoglobin levels just above thethreshold for symptoms. Mild anemia may not need treatment, as long asit doesn't worsen. Less commonly CDA-2 causes severe anemia. Treatment of severe anemia may involve blood transfusions. Blood transfusions canraise iron levels so, careful monitoring and treatment for iron overload is required.

Splenectomy is considered for people with CDA-2 and severe anemia. Splenectomy can cause a consistent rise in hemoglobin values. The spleen, however, is important in fighting infection. People, particularly children, who have had a splenectomy are more likely to contract a serious and possibly life-threatening infection (sepsis). This risk must be carefully weighed. Splenectomy does not affect iron overload.

Lastly, people with very severe CDA-2 may be candidates for hematopoietic stem cell transplantation (HSCT). Currently this is the only available curative treatment for CDA-2.