Genetic studies by NGS Panels 
Panel for Congenital sideroblastic Anaemia and acquired sideroblastic Anaemia (Code 10020)

Our laboratory performs genetic diagnoses of congenital sideroblastic anemia and acquired sideroblastic anemia.

Sideroblastic anemias are characterized by the presence of ringed sideroblasts in the bone marrow. There are two forms of sideroblastic anemia, congenital sideroblastic anemia (see congenital sideroblastic anemia) and acquired sideroblastic anemia – not hereditary – including a well-defined subtype of myelodysplastic syndrome (MDS) that present ring sideroblasts (RARS, RARS- T and RCMD-RS).


Congenital sideroblastic anemia

Congenital sideroblastic anemia (CSA) is characterized by impaired mitochondrial iron metabolism, ring sideroblast and increased erythropoiesis.

The microcytic forms of CSA are rare genetic diseases due to mutations in at least four genes: ALAS2, SLC25A38, ABCB7 and GLRX5.


The most frequent form is due to mutations in the ALAS2 gene with an X-linked inheritance, so the incidence of the disease is much higher in men than in women (OMIM # 300751). In these cases there is an ineffective erythropoiesis, presence of ring sideroblasts and usually hepatic iron overload. The clinical onset age of the disease is variable (0-90 years). These patients may respond to treatment with vitamin B6 (pyridoxine) and folic acid. In some cases of severe anemia without response to treatment support measures such as blood transfusions are necessary. Iron overload is treated with chelation therapy.

The second most common type of microcytic and non-syndromic CSA is due to mutations in the SLC25A38 gene (Guernsey et al., Nat Genet 2009) (OMIM # 301310). Deficiency of the mitochondrial SLC25A38 transporter causes severe hypochromic microcytic anemia with accumulation of iron in the mitochondria of erythroid cells, formation of excess ring sideroblasts in the bone marrow. This disease is inherited in autosomal recessive manner. This type of anemia does not respond to treatment with vitamin B6 (pyridoxine) and patients often need regular blood transfusions for their normal development. Iron overload is treated with chelation therapy. Bone marrow transplantation has been successfully performed in some patients.


Sideroblastic microcyst anemia with X-linked ataxia (XLSA/A) is a syndromic form associated with spinocerebellar ataxia, and is due to mutations in an ABCB7 gene (Allikmets R. et al, 1999) (OMIM # 301310). The ABCB7 protein is found in the inner membrane of mitochondria and is essential for hematopoiesis since it is involved in transporting structures containing groups of iron and sulfur atoms (Fe/S clusters). The deficiency of the Fe/S cluster leads to the activation of the IRP1 protein that blocks the synthesis of the ALAS2 protein, the first enzyme in the synthesis of the heme group, leading to anemia.


GLRX5 gene codes for glutaredoxin 5, a mitochondrial enzyme, with an essential role in the formation of iron/sulfur clusters (Fe/S cluster). The deficiency of this enzyme generates a mild microcytic hypochromic anemia with iron overload in the liver, an enlargement of spleen and liver and type 2 diabetes (OMIM # 610819). It is a very rare disorder, so far it has only been described in few patients and its prevalence is not known (Camaschela C. et al, 2007). The patients described with mutations in this gene do not respond to treatment with vitamin B6 (pyridoxine) or folic acid. Surprisingly, anemia worsened upon treatment with blood transfusions and was improved by iron chelation therapy.


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).


Syndromic forms (with extra-hematological affectations) of CSA are rare genetic diseases due to mutations in the genes: PUS1, YARS2, SLC19A2 or TRNT1 and are all of autosomal recessive inheritance.


Mitochondrial myopathy and sideroblastic anemia or myopathy with lactic acidosis and sideroblastic anemia (MLASA) belong to the heterogeneous family of metabolic myopathies. It is characterized by progressive intolerance to exercise that manifests itself during childhood and by the appearance of sideroblastic anemia in adolescence, as well as lactic acidemia and mitochondrial myopathy. The MLASA1 form is due to mutations in the gene coding for nuclear pseudo-uridine synthase 1 (PUS1), located at 12q24.33. Poor pseudouridination of mitochondrial tRNAs may lead to a disorder of oxidative phosphorylation. Muscle biopsy shows a low activity of complexes 1 and 4 of the respiratory chain and the possibility of paracrystalline inclusions in most mitochondria, observable by electron microscopy.


MLASA2 form (myopathy, lactic acidosis and type 2 sideroblastic anemia) is due to mutations in the YARS2 gene (Riley et al., 2010) that codes for the mitochondrial enzyme tyrosyl-tRNA synthetase. This disorder shows a marked phenotypic variability: some patients have a severe multi-systemic disorder since infancy, including cardiomyopathy and respiratory insufficiency that causes early death, while others present in the second or third decade of life with sideroblastic anemia and mild muscle weakness.


Megaloblastic anemia sensitive to thiamine (AMST) is characterized by the triad of megaloblastic anemia, non-type 1 diabetes mellitus and sensorineural deafness. Clinical manifestations of megaloblastic anemia may include hyporexia, lethargy, headache, pallor, diarrhea, and paresthesia in the hands and feet. Other variable clinical signs include: retinal dystrophy, optic nerve atrophy, short stature, cardiovascular abnormalities including congenital heart defects such as ventricular and/or atrial septal defects and conduction abnormalities / arrhythmias, seizures, and strokes. Variability of the phenotype can cause a significant delay between onset of symptoms and accurate diagnosis. It is caused by heterogeneous mutations in the thiamine high affinity transporter SLC19A2 (1q23.3). The differential diagnosis includes: Wolfram syndrome, mitochondrial disorders such as Kearns-Sayre syndrome and Pearson syndrome (see these terms), as well as vitamin B12 or folate dietary deficits.


Congenital Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is a severe form of constitutional sideroblastic anemia characterized by severe microcytic anemia, B-cell lymphopenia, panhypogammaglobulinemia, and variable neurodegeneration. It is due to mutations in the TRNT1 gene, which encodes the CCA addition enzyme (EC, which is an essential enzyme that catalyzes the addition of CCAs at the 3 ‘end of the tRNA precursors. This reaction is a fundamental prerequisite for the tRNAs to mature and to be aminoacylated in order to participate in protein biosynthesis. The disease occurs in infancy with recurrent febrile episodes, gastrointestinal disorders, developmental delay, convulsions, ataxia and sensorineural deafness. Most patients require regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement (IVIG). Hematopoietic stem cell transplantation has been successful in some of these cases.


Acquired sideroblastic anemia. Myelodysplastic syndrome with ringed sideroblasts (SF3B1 gene)

MDS are clonal disorders of hematopoietic stem cells characterized by peripheral cytopenia and the propensity to progress to acute myeloid leukemia (AML). Refractory anemia with ring sideroblasts (RARS) and refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) are two phenotypically well-defined subtypes of MDS that are characterized by ring sideroblasts.


Iron overload is common in patients with MDS and has a negative influence on survival in these patients (worse overall survival and worse leukemia-free survival). Prolonged therapy of red cell transfusions is a contributing factor to iron overload, although many patients develop an iron overload at an early stage of the disease, even before transfusions, probably due to inefficient erythropoiesis. An iron chelation therapy is therefore beneficial in these patients.

Recently, somatic mutations in the SF3B1 gene (a gene involved in RNA splicing machinery) have been reported to be particularly common (60-80%) in patients with SMD- RARS or RCMD-RS (Papaemmanuil E et al. 2011 NEJM).



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