Human Genetic Diseases

X-Linked Sideroblastic Anemia

Introduction to X-Linked Sideroblastic Anemia

Sideroblastic Anemia is a descriptive medical term referring to the combined diagnosis of anemia resulting from a reduced hemoglobin concentration and elevated iron levels stored in tissues resulting from the inability to use iron to make hemoglobin. This condition, while easy to describe, has been hard to categorize with respect to the actual cause of the disorder. It can be inherited or it can be secondary either to other disorders or to chemicals and drugs.

Recently, some of the confusion in this field has been reduced with the discovery that mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2) are the cause of X-linked sideroblastic anemia (XLSA). A variety of different point mutations in the ALAS2 gene have been found in unrelated patients with XLSA, explaining in part the observed clinical heterogeneity. Since ALAS2 is the first and rate-limiting enzymatic step in the biosynthesis of heme in the bone marrow, deficient activity of this enzyme leads to low concentrations of the penultimate metabolite in the heme biosynthetic pathway, protoporphyrin IX, and thus insufficient porphyrin to utilize the iron being husbanded by the body for the synthesis of heme. The excess iron, which is not excreted by the body, then accumulates over years in 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 arthritic signs. A partial listing of the specific mutations in the ALAS2 gene that cause X-linked sideroblastic anemia has been compiled by the Human Gene Mutation Database in Cardiff, UK.

In addition, some of the variation in severity of the disorder can now be understood as being a result of the concurrent inheritance of a hemochromatosis gene mutation, which also causes storage of iron.

For a review of X-linked sideroblastic anemia, see our article in The Metabolic and Molecular Bases of Inherited Diseases

Research on X-linked sideroblastic anemia is being carried out by Dr. David F. Bishop in the Department of Genetics and Genomic Sciences at the Mount Sinai School of Medicine.