Non Sideroblastic Anemias
Non sideroblastic Microcytic hypochromic anaemias
Microcytic anaemia is the most frequent anemia observed in general medical practice. Nutritional iron deficiency and beta thalassemia trait are the primary causes in pediatrics, whereas bleeding disorders and anemia of chronic diseases are common in adulthood. Microcytic hypochromic anaemia can be a result from a defect in the globin genes, the synthesis of heme, the availability and/or acquisition of iron by erythroid precursors. Our laboratory performs genetic diagnosis of microcytic anaemias due to inherited defects in heme synthesis or defects in iron metabolism.
Aceruloplasminemia (OMIM # 3604290) is an autosomal recessive disorder caused by mutations in the gene encoding ceruloplasmin (CP), which is the major copper transport protein in plasma and is also involved in iron release from macrophages and other cells into the bloodstream. Clinical manifestations of the disease include low levels or absence of serum ceruloplasmin, low serum copper and iron, high serum ferritin, microcytic anemia, mild to moderate iron accumulation in the liver, pancreas and basal ganglia, diabetes mellitus and late-onset neurological symptoms. About 60 patients worldwide have been diagnosed with this disease. The estimated prevalence of the disease is <1 per 2000000. Iron overload can be reduced by phlebotomy, but there is no established treatment for neurological symptoms.
Atransferrinemia or hypotransferrinemia is an autosomal recessive rare disorder, due to mutations in the gene encoding for transferrin (TF), resulting in a sharp reduction in its synthesis (OMIM # 209300). Transferrin is the plasma protein that transports iron in the blood. Laboratory values of TF are usually half the normal range (204-360 mg / dl) in carriers and very low in affected patients (total absence is incompatible with life). This reduction in levels of TF leads to a decrease in the delivery of iron to the bone marrow, which affects the development of erythroid precursors, resulting in reduced hemoglobin synthesis, and accumulation of excess iron in peripheral tissues. Affected patients present with severe microcytic hypochromic anemia from the neonatal period or infancy, growth retardation and recurrent infections. Iron overload occurs mainly in liver, joints, heart, pancreas, thyroid, kidney and bone, leading to symptoms such as liver failure, heart problems, joint disease and hypothyroidism. It is estimated that the prevalence of this disease is <1/1 million.
Mutations in the SLC11A2 gene cause a deficiency of divalent metal transporter 1 (DMT1) and a hypochromic microcytic anemia with iron overload (AHMIO1 OMIM # 206100). DMT1 is an important carrier for duodenal iron absorption and for the transfer of iron from the endosomes to the cytosol of developing erythroid cells. DMT1 deficiency leads to severe hypochromic microcytic anemia present at birth with progressive overload, hepatic iron levels associated with normal to moderately elevated ferritin in serum. This disease is autosomal recessive and the exact prevalence is unknown, but is estimated at <1/1 000 000. Patients diagnosed with this disease have been treated with transfusions of red blood cells.
Iron-Deficiency Anemia Iron-Refractory (IRIDA) is an autosomal recessive disorder due to mutations in the TMPRSS6 gene (OMIM # 206200). This gene encodes the protein Matriptase-2, a serine protease with an important role in intestinal iron absorption. TMPRSS6 mutations cause a reduction in the activity of the Matriptase-2 in hepatocytes and an increase in levels of hepcidin hormone which in turn inhibits intestinal iron absorption, which leads to a moderate hypochromic microcytic anemia at birth. This anemia is unresponsive to treatment with oral iron but there is a partial response to intravenous iron therapy that should be given especially during the growth stage. The estimated prevalence of this disease is <1/1 000 000.