Congenital dyserythropoietic anemia type I
Description, Causes and Risk Factors:
Abbreviation: CDA I
Congenital dyserythropoietic anemia type I (CDA I) is a rare autosomal recessive disorder with ineffective erythropoiesis and iron overloading. CDA I is characterized by moderate to severe anemia. It is usually diagnosed in childhood or adolescence, although in some cases, the condition can be detected before birth. Many affected individuals have yellowing of the skin and eyes (jaundice) and an enlarged liver and spleen (hepatosplenomegaly
). 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 Congenital dyserythropoietic anemia type I are born with skeletal abnormalities, most often involving the fingers and/or toes.
The disorder follows an autosomal recessive trait. Two people who carry each one copy of one of the mutated gene have a 25% risk of having a child affected by the disorder at each pregnancy. The risk of having a child who is a healthy carrier of the disorder is 50% at each pregnancy, and the risk that a child will not have the disorder and will not be a carrier is 25 %.
The gene responsible for Congenital dyserythropoietic anemia type I (CDAN1 gene) has been mapped to the long arm of chromosome 15 between 15q15.1q15.3 by homozygosity mapping in four Bedouin families with a high degree of consanguinity and could be assigned to an 0.5-cM interval. 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. Similar results were reported in six patients from Europe and the Near East. Within the Congenital dyserythropoietic anemia type I linkage interval 15 putative genes expressed in erythroblasts were identified. The CDAN1 gene was recently cloned with 28 exons spanning 15 kb encoding a protein named codanin-1. In nine unrelated patients of European, Bedouin, and Asian origin different point mutations were detected in the codanin-1 gene. Further work is in progress to decide whether all families with the CDA I phenotype are related to codanin-1 mutations as well as studies to define the role of the codanin-1 protein for normal erythropoiesis, possibly involved in maintaining the integrity of the nuclear membrane. DNA synthesis becomes arrested in the S-phase of such cells. The same is true for cells in disk lost gene Drosophila mutants, which produce a codanin-1-like protein.
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.
: A total of 842 genes were differentially expressed in CDA I patients: 383 genes were up-regulated and 459 genes were down-regulated. The array revealed a 100 fold overexpression of H19 in CDAI patients. H19 expression is controlled by methylation of an imprinting control region. Researchers studied the imprinting status of H19 in CDAI samples and found monoallelic expression of H19. Methylation of the imprinting control region was also similar to unaffected control.
Symptoms of Congenital dyserythropoietic anemia type I :
Almost all affected individuals have a chronic moderate anaemia, which does not impair life expectancy, but may impair ability on exertion. In some patients, quality of life and functional ability will again be reduced in higher age, particularly when the function of the heart or the lungs are impaired. Additional symptoms are yellow discoloration in the eyes and sometimes of the skin. The spleen becomes enlarged, although the enlargement remains without symptoms. Other possible consequences are leg ulcers or bulks of extramedullary erythropoiesis along the spine seen in x-ray of the thorax, which may cause difficulties of diagnosis.
Diagnosis Congenital dyserythropoietic anemia type I :
The diagnosis of congenital dyserythropoietic anemia type I (CDA I) is based on the findings of:
Macrocytic anemia: Moderate to severe with MCV (mean corpuscular volume) >90.
Bone marrow aspirate:
Peripheral blood smear: Macrocytosis, elliptocytes, basophilic stippling, and occasional mature nucleated erythrocytes.
Reticulocytes: Inappropriately low for the degree of anemia compared to other hemolytic anemias (secondary to ineffective erythropoiesis)
- Electron microscopy: Erythroid precursors with spongy appearance of heterochromatin (in ?60% of erythroblasts) and invaginations of the nuclear membrane.
- Light microscopy: Erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts.
In severe forms the anemia may be severe enough to require regular blood transfusion in childhood. In most cases, the anemia becomes less severe in adolescents or adulthood, and regular transfusions beyond childhood are only rarely necessary. In cases which require regular blood transfusions, or when the physical ability and quality of life is impaired, treatment by interferon alpha, a normal hormone of the body can normalize the blood counts. This alleviates symptoms and prohibits further iron uptake. If indicated, this treatment has to be used for long times, possibly life long, with weekly or biweekly injections. This type of treatment has to be controlled by a specialist of Paediatric or Internal Medicine, who has experience with the treatment of chronic anemias.
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.