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Congenital Sideroblastic Anemia
Monday, 18 August 2003
Sunday, 28 November 2004
X-linked Sideroblastic Anemia, Hereditary Iron-Utilization Anemia


The sideroblastic anemias are a group of rare blood disorders characterized by the bone marrow's inability to manufacture normal red blood cells. The main defect is a failure of red blood cell (RBC) precursors to use iron in hemoglobin synthesis, despite the availability of adequate iron stores. As a result, iron is deposited in these RBC precursors forming the characteristic “ringed sideroblast” as seen under a microscope (‘sidero,’ meaning iron, and ‘blast’, meaning a precursor or an early germ cell that is still able to differentiate). The iron deposits are damaging to the cell, causing sideroblasts to develop poorly, if at all, into mature red cells. These factors along with the defective production of hemoglobin, a molecule that carries oxygen in the blood, results in anemia. Anemia (literally means ‘lacking blood’) simply indicates a decrease in RBCs in the blood. This is usually measured by a decrease in hemoglobin and can result in paleness, fatigue, and breathlessness due to the decrease in oxygen transport. There are two main types of sideroblastic anemia: congenital (inherited) or acquired. Congenital sideroblastic anemia (CSA) is the focus of this article and is usually inherited through a mutation of a gene on the X chromosome, making it an X-linked disorder.


Congenital sideroblastic anemia is very rare and only several hundred cases have been reported worldwide. It disproportionately affects males because it takes only one abnormal X chromosome for males to develop disease. The age of disease onset can be variable- some children develop anemia within a few months of life while others may not have symptoms until 7 or 8 years-old. Females with one copy of an affected X chromosome show no signs of disease and are termed “silent carriers.” There are a few patients who develop sideroblastic anemia as part of a metabolic syndrome or disease. Examples include: Rogers syndrome (defect in thiamine transport) and Pearson syndrome (bone marrow and pancreatic failure).

Signs and Symptoms

In CSA, the symptoms usually appear early, within the first few months or years of life and prior to age thirty. General presentation of sideroblastic anemia includes pale skin, fatigue, dizziness, and difficulty breathing. Excessive levels of iron in the blood, or iron toxicity, may lead to iron accumulation in various organs, resulting in severe complications such as heart disease (ie. congestive heart failure, irregular heartbeat, recurring inflammation of the sac that surrounds the heart), liver damage (liver nodules and scar tissue), kidney failure, and an enlarged spleen, liver and lymph nodes. Additional potential complications of sideroblastic anemia include: diabetes mellitus, secondary hypopituitarism (dwarfism), jaundice (yellowing of the skin), and underactivity of the thyroid gland.

Possible Causes

Congenital sideroblastic anemia may be caused by mutations in two key iron-related genes: the ATP7 gene and the ALAS2 gene, which are located on the X-chromosome, one of the two sex chromosomes. Mutations in ALAS2 have been found in many patients with CSA. Normally, ALAS2 makes an enzyme called ALA-synthase, which is critical to proper heme production in the bone marrow. Heme is the vital component of hemoglobin, within a RBC, that actually carries the oxygen. If the ALAS2 gene is mutated, heme production is abnormal. As a result not enough hemoglobin is made, and iron (which normally binds to hemoglobin) can build up and damage the body's tissues. The excess iron accumulates for years in the bone marrow, liver, heart, and other tissues. This progressive deposition of toxic iron results in the major clinical presentations of cirrhosis of the liver, heart disease, diabetes, impotence, and early signs of arthritis. In addition, people who inherit a mutation in the HFE gene along with a mutation in the ALAS2 gene may experience more severe symptoms of the disorder. Mutations in the HFE gene cause hemochromatosis, which is marked by iron accumulation in the body as a result of excessive iron absorption from the gastrointestinal tract.


This disorder is usually diagnosed using blood tests that may reveal low hemoglobin levels, high iron levels, and red blood cells that are smaller and paler than normal. A bone marrow aspirate stained with a blue dye may present the characteristic “ringed sideroblasts,” the abnormal red blood cell precursors containing peripheral iron deposits. Genetic testing can identify mutations in the ALAS2 gene and other related genes that are suspected to cause the disorder, but this test is currently available only on a research basis.


Treatment for sideroblastic anemia depends on the underlying cause. In CSA, blood transfusions and a drug called pyridoxine (vitamin B6) can increase hemoglobin levels in the blood to relieve anemia-related symptoms such as fatigue. These measures are not curative however, and patients who endure iron-overload from repeated blood transfusions sometime require “chelation” therapy with desferrioxamine (Desferal) to help stimulate excretion of excess iron through urine and feces. Bone marrow transplantation has been an effective treatment for a small number of patients.


Children with congenital sideroblastic anemia have variable responses to therapy however most children improve little with medical intervention. Some forms of sideroblastic anemia can even progress to leukemia over the course of decades. Supportive care is the mainstay in severely affected patients.

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Iron Disorders Institute
Great overview, publications, news and medical glossary.

Family Practice Notebook
Brief outline of SA with hotlinks of each medical term.
Nice summary of X-linked SA, links to other genetics resources-recent research, clinical studies, etc., glossary for medical terms.

Google Search for Congenital Sideroblastic Anemia

References and Sources

Harmening, D. Clinical Hematology & Fundamentals of Hemostasis 4th ed., c.2002. P.105-7 Nathan, D., et al. Hematology of Infancy and Childhood. 6th ed. C 2003 P. 482-491.