Our laboratory performs genetic diagnosis of congenital microcytic type (low hemoglobin and low VMC <80fl) sideroblastic anemia.
Congenital sideroblastic anemia (CSA) is characterized by an alteration of mitochondrial iron metabolism, presence of ringed sideroblasts and increased erythropoiesis. Microcytic forms of CSA are rare genetic diseases due to mutations in at five genes: ALAS2, SLC25A38, ABCB7, GLRX5 and STEAP3.
The most common is due to mutations in the ALAS2 gene that has an X-linked inheritance, so the incidence is much higher in men than in women (OMIM # 300751). In these cases there is ineffective erythropoiesis, presence of ringed sideroblasts and normal hepatic iron overload. The age of clinical onset of the disease is variable (from 0 to 90 years). These patients may respond to treatment with vitamin B6 (pyridoxine) and folic acid. In some cases of severe anemia without response to treatment supportive measures such as blood transfusions are necessary. Iron overload is treated with chelation therapy.
The second most common type of microcytic and nonsyndromic CSA is due to mutations in the SLC25A38 gene (Guernsey et al., Nat Genet, 2009) (OMIM # 301310). Deficiency of the mitochondrial transporter SLC25A38 causes severe hypochromic microcytic anemia with iron accumulation in mitochondria of erythroid cells and formation of excess ring sideroblasts in the bone marrow. It has an autosomal recessive inheritance. This type of anemia does not respond to treatment with vitamin B6 (pyridoxine) and patients often need regular blood transfusions for normal development. Iron overload is treated with chelation therapy. Bone marrow transplantation has been carried out successfully in some patients.
Microcytic sideroblastic anemia with ataxia linked to chromosome X (XLSA / A) is a syndromic form associated with spinocerebellar ataxia, and may be due to mutations in the ABCB7 gene (Allikmets R. et al, Hum Mol Gen, 1999) (OMIM # 609588). ABCB7 protein is found in the inner membrane of mitochondria and it is essential for hematopoiesis and is involved in the transport of structures that contain groups of iron and sulfur atoms (Fe/S clusters). Deficiency of Fe/S clusters produces activation of IRP1 protein that blocks ABCB7 protein synthesis, the first enzyme of the heme synthesis, leading to anemia.
GLRX5 gene encoding glutaredoxin GLRX 5, a mitochondrial enzyme with an essential role in the formation of iron/sulfur clusters (Fe/S clusters). Deficiency in this enzyme produces a mild microcytic hypochromic anemia with iron overload in the liver, an enlarged spleen and liver and diabetes type 2 (OMIM # 610819). It is a very rare disorder, so far it has only been described in one patient and its prevalence is unknown (Camaschela C. et al, 2007). The patient described with a mutation in this gene does not respond to treatment with vitamin B6 (pyridoxine) and folic acid. Surprisingly anemia in this patient worsened with a treatment with blood transfusions and improved by iron chelation therapy.
The first case of a novel genetic form of severe and transfusion-dependent hypochromic anemia associated with a nonsense mutation of the STEAP3/TSAP6 gene (AHMIO2 OMIM #609671) (Grandchamp et al., Blood, 2011) has recently been reported. The clinical phenotype of these patients resembles some aspects of cases of non-syndromic congenital sideroblastic anemia (CSA) (sideroblasts and iron overload). However, erythrocyte protoporphyrins are increased in this family, while they are at normal or even low levels in CSA linked to either ALAS2 or SLC25A38 mutations. Electron microscopy demonstrated the accumulation of iron in both siderosomic granules and mitochondria. This gene encodes a 6-transmembrane epithelial antigen of the prostate (Steap3) protein that is involved in the regulation of the cell cycle, apoptosis and the secretion of proteins via a non-classical pathway including the exosomes. In the pathway for iron uptake, the STEAP3/TSAP6 encodes a ferrireductase involved in the acquisition of iron by developing red blood cells, and it is highly expressed in hematopoietic tissues where it localizes to the specialized endosome. Steap3/tsap6 null-mice display severe hypochromic microcytic anemia and abnormal reticulocyte maturation, with impaired secretion of the transferrin receptor caused by a decreased production and secretion of exosomes (Ohgami et al., Blood, 2005).