Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


X - linked sideroblastic anemia (X-linked sideroblastic anemia) - Genes ALAS2 HFE

Sideroblastic anemia X - linked, is an inherited disorder that prevents the development of red blood cells and sufficient production of hemoglobin. People with sideroblastic anemia have X - linked hypochromic microcytic and mature erythrocytes due to deficiency of hemoglobin and an abnormal iron accumulation in erythrocytes. Erythroblasts loaded with iron, which are present in bone marrow, are called sideroblasts, and therefore called thus this anemia. Signs and symptoms of sideroblastic anemia X - linked are due to a combination of decreased hemoglobin and iron overload. These signs and symptoms can be mild or deep, they appear more frequently in adulthood. Common manifestations include fatigue, dizziness, rapid heartbeat, pale skin and hepatomegaly. Over time, the manifestations are more intense, affecting the heart or liver, resulting from the accumulation of excess iron in these organs.

This process is due to mutations in the ALAS2 gene, located on the short arm of chromosome X (Xp11.21). This gene encodes the enzyme ALA synthase-erythroid (5-aminolevulinate synthase 2), which plays an important role in heme synthesis. Heme is vital to all organs of the body, but is most abundant in the blood, bone marrow and liver. Another ALAS1 (ALA synthase) gene is active in cells throughout the body. However, the ALAS2 gene is only active in the development of erythroblasts. Heme production is a multistep process that requires eight different enzymes. ALA synthase enzyme is responsible for the first stage of this process, the formation of a compound called delta-aminolevulinic acid (ALA). In later stages, seven enzymes produce and modify compounds that eventually give rise to heme.

Have identified at least 50 mutations in the gene ALAS2 in people with sideroblastic anemia X - linked. Almost all of these mutations change the amino acids of the erythroid-ALA-synthase. These changes alter the activity of the enzyme, which disrupts the normal production of heme in the development of blood erythrocytes. A reduction in the amount of heme prevents these cells develop enough hemoglobin. Because almost all the iron transported erythroblasts normally incorporated heme, reduced production of heme causes an accumulation of excess iron in these cells. In addition, the body tries to compensate for the deficiency of hemoglobin by absorbing more iron from the diet. This excess iron can damage organs in the body. Low concentrations of hemoglobin and the subsequent accumulation of iron in body organs leads to the characteristic features of the X - linked sideroblastic anemia

Some Cys282Tyr carriers of the mutation in another gene called HFE, along with a mutation in the gene ALAS2 may present a more intense form of X - linked sideroblastic anemia In this rare situation, the combined effect of these two mutations can cause an overload of iron worse. Mutations in the HFE gene alone may increase the absorption of dietary iron resulting hemochromatosis, other alteration of iron overload.

The HFE gene located on the short arm of chromosome 6 (6p21.3), encodes a protein found on the surface of cells, primarily in the intestinal cells in the liver and in some cells of the immune system. The HFE protein interacts with other proteins on the cell surface to detect the amount of iron in the body. The HFE protein regulates production of another protein called hepcidin, which is considered the iron regulatory hormone. Hepcidin is produced by the liver, and determines the amount of iron absorbed from the diet and released from storage sites in the body. When the proteins involved in the detection and iron absorption are functioning properly, iron absorption is regulated. On average, the body absorbs about 10% iron obtained from the diet. The HFE protein also interacts with two proteins called transferrin receptors; however, the role of these interactions in regulating iron is unclear.

Sideroblastic anemia X - linked inherited recessive pattern with an X - linked In males, an altered copy of the gene in each cell is sufficient to express the disease. In women, the mutation would have to happen in both copies of the gene for the disease to be expressed. Because it is unlikely that women have the mutation on both X chromosomes, males are affected by X - linked recessive disorders much more frequently than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome.

Tests in IVAMI: in IVAMI perform detection of mutations associated with X - linked sideroblastic anemia, by complete PCR amplification of the exons of ALAS2 HFE, respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).