Genetic studies by NGS Panels
Panel for Iron-related Anemia (including IRIDA, atransferrinemia, aceruloplasminemia, AHMIO1 and AHMIO2) (Code 10030)
Hypochromic and microcytic anemias due to defects in iron metabolism genes
Microcytic anemia is the anemia most frequently observed in general medical practice. Iron deficiency and thalassemia beta trait are the leading causes in pediatrics, whereas coagulation disorders and anemia of chronic diseases are common in adulthood. Microcytic hypochromic anemia may be the result of a defect in the globin genes, heme synthesis, the availability of iron, or the acquisition of iron by erythroid precursors. Our laboratory performs genetic diagnoses of hereditary microcytic anemia due to defects in iron metabolism.
Aceruloplasminemia (OMIM # 3604290) is an autosomal recessive disorder due to mutations in the gene encoding ceruloplasmin (CP), the main plasma copper transporter protein, which is involved in the release of iron from macrophages and other cells to the bloodstream. Clinical manifestation of the disease includes low levels or absence of serum ceruloplasmin, low levels of serum copper and iron, elevated serum ferritin, mild to moderate microcytic anemia, iron overload 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. (Kono S. Int Rev Neurobiol. 2013).
Atransferrinemia or hypotransferrinemia is a very rare autosomal recessive disorder, due to mutations in the gene that codes for Transferrin (TF), producing a strong reduction of its synthesis (OMIM # 209300). Transferrin is the plasma protein that carries iron in the blood. The laboratory values of TF are usually half the normal values (204-360 mg / dl) in carriers and very low in affected patients (total absence of TF is incompatible with life). This reduction in TF levels leads to a decrease in the delivery of iron to the bone marrow for the development of erythroid precursors, resulting in a reduced hemoglobin synthesis, and in the accumulation of excess iron in peripheral tissues. Affected patients present with severe microcytic hypochromic anemia from the neonatal or childhood period, grow retardation and recurrent infections. Iron overload occurs mainly in the liver, joints, heart, pancreas, thyroid, kidney and bone, leading to symptoms such as liver failure, heart problems, arthropathy and hypothyroidism. The prevalence of this disease is estimated to be <1/1 000 000. (Athiyarath R., et al, Br J Haematol., 2013)
Mutations in the SLC11A2 gene produce a deficiency of the divalent metal transporter 1 (DMT1) and a microcytic and hypochromic anemia with iron overload (AHMIO1 OMIM # 206100). DMT1 is a major transporter for the absorption of duodenal iron and for the transfer of iron from the endosomes to the cytosol of the developing erythroid cells. Deficiency of DMT1 leads to severe hypochromic microcytic anemia present from birth with progressive overload of hepatic iron associated with severely elevated serum ferritin levels. This disease has an autosomal recessive inheritance and its prevalence is unknown but is estimated at <1 / 1,000,000. Patients described with this disease have been treated with red blood cell transfusions. (Iolascon A, et al., Blood. 2006).
Iron-refractory Iron-Deficiency Anemia (IRIDA) is an autosomal recessive disorder due to mutations in the TMPRSS6 gene (OMIM # 206200). This gene encodes for the protein matriptase-2, a serine protease with an important function in the absorption of iron. Mutations in the TMPRSS6 gene produce a decrease in the activity of matriptase-2 in hepatocytes and a greater amount of the hormone that inhibits iron absorption, hepcidin, leading to moderate hypochromic microcytic anemia from birth. This anemia is refractory (no response) to treatment with oral iron and partially responds to treatment with intravenous iron that should be administered especially during the growth stage. The estimated prevalence of this disease is <1 / 1,000,000. (De Falco L, et al., Haematologica. 2013; De Falco L., et al., Hum Mutat. 2014).
Recently the first case of a new form of hypochromic and transfusion-dependent anemia associated with a nonsense mutation of the STEAP3/TSAP6 gene (AHMIO2 OMIM # 609671) (Grandchamp et al., Blood, 2011) has been described. The clinical presentation of the patients was in some respects similar to that of non-syndromic sideroblastic anemia (CSA) with presence of sideroblasts and iron overload. However, in this family, protoporphyrin levels are increased, while they are normal or even low in cases of CSA linked to mutations in the ALAS2 or SLC25A38 genes. Electron microscopy shows accumulation of iron in both siderosomal granules and mitochondria. This gene codes for prostate transmembrane epithelial antigen (steap3) that is involved in regulation of cell cycle, apoptosis, and in the secretion of non-classical proteins, including exosomes. In iron metabolism, the STEAP3 / TSAP6 gene codes for a ferrireductase involved in the absorption of iron by red blood cells; this protein is highly expressed in hematopoietic tissues where it is located in the endosome. Mice lacking the Steap3/Tsap6 gene exhibit severe microcytic hypochromic anemia and abnormal reticulocyte maturation, with the endocytic pathway of the affected transferrin receptor due to decreased production of exosomes (Ohgami et al., Blood, 2005).
- Athiyarath R, Arora N, Fuster F, Schwarzenbacher R, Ahmed R, George B, Chandy M, Srivastava A, Rojas AM, Sanchez M, Edison ES. Two novel missense mutations in iron transport protein transferrin causing hypochromic microcytic anaemia and haemosiderosis: molecular characterization and structural implications. Br J Haematol. 2013 Nov;163(3):404-7. [PubMed PMID: 23888904].
- De Falco L, Sanchez M, Silvestri L, Kannengiesser C, Muckenthaler MU, Iolascon A, Gouya L, Camaschella C, Beaumont C. Iron refractory iron deficiency anemia. Haematologica. 2013 Jun;98(6):845-53. Review. [PubMed PMID: 23729726].
- De Falco L, Silvestri L, Kannengiesser C, Morán E, Oudin C,Rausa M, Bruno M, Aranda J, Argiles B, Yenicesu I, Falcon-Rodriguez M, Yilmaz-Keskin E, Kocak U, Beaumont C, Camaschella C, Iolascon A, Grandchamp B, Sanchez M. Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies. Hum Mutat. 2014 Nov;35(11):1321-9. [PubMed PMID: 25156943].
- Grandchamp B, Hetet G, Kannengiesser C, Oudin C, Beaumont C, Rodrigues-Ferreira S, Amson R, Telerman A, Nielsen P, Kohne E, Balser C, Heimpel H. A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood. 2011 Dec 15;118(25):6660-6. [PubMed: 22031863].
- Iolascon A, d’Apolito M, Servedio V, Cimmino F, Piga A, Camaschella C. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood. 2006 Jan 1;107(1):349-54. [PubMed PMID: 16160008].
- Kono S. Aceruloplasminemia: an update. Int Rev Neurobiol. 2013;110:125-51. Review. [PubMed PMID: 24209437].
- Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005 Nov;37(11):1264-9. [PubMed: 16227996].