Sideroblastic anemias are a heterogeneous group of disorders characterized by anemia of varying severity and diagnosed by finding ring sideroblasts in the bone marrow aspirate. The peripheral blood shows hypochromic red cells, which are microcytic in the hereditary forms (Fig. 1A) but are often macrocytic in the acquired forms of the disease. The red blood cell parameters from automated cell counting may show bimodal volume distribution curves or widened range of cell sizes (see Fig. 1B); however, this dimorphic size distribution is not always present. Tiny inclusions may be visible in the red blood cells; these can be confirmed as iron-containing Pappenheimer bodies by Prussian blue staining of the blood smear (see Fig. 1C). The diagnostic test is bone marrow examination together with Prussian blue staining of the bone marrow smears.

Fig1. (A) Peripheral blood smear from a patient with hereditary sideroblastic anemia shows a population of hypochromic and microcytic erythrocytes. (B) Erythrocyte volume distribution curve of a patient with hereditary sideroblastic anemia. A dimorphic size distribution is evident. (C) Peripheral blood showing Pappenheimer bodies (Prussian blue stain). (D) The bone marrow smear stained with Prussian blue shows ring sideroblasts.

The presence of ring sideroblasts (see Fig. 1D) is defined as erythroblasts containing five or more iron-positive (siderotic) gran ules arranged in a perinuclear collar distribution around one-third or more of the nucleus. Electron microscopic examination has shown that these siderotic granules are mitochondria containing amorphous deposits of ferric phosphate and ferric hydroxide. Iron is also bound to mitochondrial ferritin, a molecular form of ferritin that can be distinguished from cytoplasmic ferritin and that accumulates in large amounts in the erythroblasts of subjects with impaired heme synthesis.

Iron overload is a common clinical feature of refractory sideroblastic anemia and, in severe cases, may lead to complications that characterize secondary hemosiderosis (e.g., diabetes, cardiac failure). Marrow examination shows prominent erythroid hyperplasia, which is a sign of the ineffective erythropoiesis and is responsible for increased iron absorption by a mechanism that may involve the erythroid factor erythroferrone suppressing hepcidin production. The sideroblastic anemias have diverse causes but have in common an impaired biosynthesis of heme in the erythroid cells of the mar row. Most sideroblastic anemias are acquired as a clonal disorder of erythropoiesis, with various degrees of myelodysplastic features (Table1). The inherited forms are uncommon and occur predominantly in males with an X-linked pattern of inheritance. A number of drugs have been associated with reversible sideroblastic anemia, and ring sideroblasts may be found in patients who abuse alcohol (see Table 1). The first descriptions of ring sideroblasts in association with chronic refractory anemias appeared in the late 1950s, after an earlier description of familial X-linked hypochromic microcytic anemia.

Table1. Classification of Sideroblastic Anemias

Hereditary Sideroblastic Anemia

 X-Linked Sideroblastic Anemia

Biologic and Molecular Aspects

Almost 40% of congenital sideroblastic anemias are molecularly unexplained. Erythroid cells from patients with X-linked forms of hereditary sideroblastic anemia generally exhibit low activity of ALAS2; however, for a minority of ALAS2 mutations this effect may be difficult to detect in vitro. A defect in this enzyme is firmly established in patients whose anemia responds to pyridoxine therapy, because pyridoxal phosphate is an essential cofactor for ALAS2. However, even affected female patients with moderate anemia unresponsive to pyridoxine have been documented to have low levels of ALAS2 in bone marrow lysates. In some male patients with X-linked pyridoxine-responsive sideroblastic anemia, the low ALAS2 activity in bone marrow increased to levels above the normal range when the patient took pyridoxine supplements and recovered from the anemia. There are several possible explanations for this enhancement of ALAS2 activity by dietary pyridoxine supplements. The most likely is that pyridoxine (or its phosphate) may stabilize the ALAS2 during folding of the mutant enzyme after its synthesis. The gene for the ALAS2 isoenzyme has been localized to the X chromosome, and this gene is known to be the site of most mutations giving rise to X-linked pyridoxine-responsive sideroblastic anemia. Approximately 100 different mutations have been identified in individuals or families with hereditary sideroblastic anemia, and nearly all have resulted from single base alterations in DNA. A frequent mutation affects arginine at residue 452 of ALAS2, which occurs in a quarter of all pedigrees but does not affect enzyme activity measured in vitro. All known mutations lie between exons 5 and 11 of ALAS2, the region that codes for the catalytic domain, with most lying within exon 9, which contains the lysine at which binding of pyridoxal 5′-phosphate occurs. A mutation, Asp190Val, has been described in a pyridoxine-refractory patient and appears to affect the proteolytic processing of the ALAS2 during or after import into the mitochondrion. The variety of different mutations in the erythroid ALAS2 gene responsible for X-linked sideroblastic anemia and their pyridoxine responsiveness were reviewed in 2019.

Genetic Aspects

 In most families with hereditary sideroblastic anemia, males are affected with an X-linked pattern of inheritance (Fig. 2). However, female carriers, although usually normal, can develop erythrocyte dimorphism or varying degrees of anemia. The assignment of the gene for erythroid ALAS2 to the X chromosome and the many mutations documented in erythroid ALAS2 provide the genetic basis for this X-linked disease. In several families, coinheritance of other X-linked traits (e.g., glucose-6-phosphate dehydrogenase [G6PD] deficiency, ataxia with sideroblastic anemia) has been described. Sporadic and familial cases have been described that affect only females, which has been shown to represent skewed X-chromosome inactivation (“unfortunate skewing”) affecting the normal allele for the ALAS2 gene. The absence of affected male members in these pedigrees suggests that the ALAS2 defects identified are lethal in hemizygous males.

Fig2. PEDIGREE OF A FAMILY WITH PYRIDOXINE RESPONSIVE SIDEROBLASTIC ANEMIA SHOWING X-LINKED RECESSIVE INHERITANCE. Affected (filled box), carrier (filled circle within open circle), and unknown status (question mark within circle or box) are indicated. Diagonal lines indicate deceased members. This pedigree has been abbreviated to show only the affected branches of the family. The arrow indicates the proband.

Clinical and Laboratory Evaluation.

 Typically the anemia of X-linked sideroblastic anemia manifests in infancy or childhood, but the milder forms of anemia may not be found until midlife. Even elderly patients have been diagnosed with this anemia. Some cases may be discovered only during family surveys, which should always be undertaken when hereditary sideroblastic anemia is diagnosed. Still other patients may present with features of iron overload, such as diabetes or cardiac failure. Iron overload occurs commonly even with mild anemia and may occasionally be seen with female carriers. Enlargement of the liver and spleen may occur with mild abnormalities of liver function tests.

Anemia is extremely variable, but even when little or no anemia is present, the mean corpuscular volume (MCV) is low, and the red cell volume distribution width may be increased. When anemia is severe, the MCV may be as low as 50 fL (50 μm3). The blood smear shows a population of cells with hypochromic, microcytic morphology (see Fig. 1), which contrasts with the other normochromic, normocytic cells (i.e., dimorphism). Anisocytosis, poikilocytosis, elongated cells, and siderocytes may also be seen. The characteristic erythrocyte dimorphism is most prominent in patients with milder anemia, in female carriers, and in patients in whom pyridoxine has corrected the anemia but not restored the MCV to normal. In some pedigrees with only affected females, macrocytosis may be present, which contrasts with the typical microcytosis of male hemizygotes. Leukocyte values are normal, whereas the platelet count is normal or increased.

Serum iron concentration is increased, and transferrin shows an increased percentage of saturation with iron. Serum ferritin levels are invariably increased. Ineffective erythropoiesis can be confirmed by ferrokinetic measurements showing that plasma iron clearance is rapid, with subnormal retention of the iron isotope in erythrocytes after 10 to 14 days. Other features of ineffective erythropoiesis may be variably present: a mild increase in bilirubin concentration, decrease in haptoglobin levels, mild increase in lactate dehydrogenase levels, and normal or slight increase in reticulocyte numbers. The magnitude of iron overload correlates poorly with the degree of anemia in patients who are not transfused. The degree of ineffective erythropoiesis is a better predictor of the amount of iron overload. When ferrokinetics are unavailable, the extent of erythroid hyperplasia relative to normal acts as a rough measure of the magnitude of ineffective erythropoiesis. Several studies have shown that the relative increase in erythroid activity multiplied by the patient’s age shows a good correlation with the degree of iron overload as measured by plasma ferritin. The iron overload does not result from mutations in the HFE gene.

Differential Diagnosis

Hereditary sideroblastic anemia should be distinguished from idiopathic hemochromatosis, because both have biochemical evidence of iron overload and a similar tissue pattern of iron deposition. Careful hematologic assessment of patient and family members should make the distinction, because the hemoglobin level and MCV are normal in idiopathic hemochromatosis.

Other Nonsyndromic and Syndromic Hereditary Sideroblastic Anemias

X-linked sideroblastic anemia is considered the most common inherited sideroblastic anemia; however, a number of rare forms have been identified. These consist of nonsyndromic sideroblastic anemias, which cause defects in either heme synthesis or iron-sulfur cluster biogenesis and have similar phenotypes to X-linked sideroblastic anemia, and syndromic forms that cause defective mitochondrial protein synthesis or structure and affect a variety of other tissues in addition to red cells.

Of the nonsyndromic forms, inherited mutations in SLC25A38, the iron-sulfur cluster biogenesis genes, GLRX5 and HSPA9, and FECH have been identified to cause autosomal recessive pyridoxine refractory sideroblastic anemias.SLC25A38 is located on chromosome 3p22.1 and encodes a mitochondrial carrier protein that may function to import glycine into the mitochondrion or exchange glycine for 5-aminolevulinate. Homozygous or compound hetero zygote mutations in SLC25A38 result in a similar phenotype to that seen in X-linked sideroblastic anemia, with onset in infancy of a severe microcytic anemia that is refractory to treatment with pyridoxine and folic acid. GLRX5 encodes a mitochondrial protein, glutaredoxin 5, which when deleted in the zebrafish mutant shiraz results in defective iron-sulfur cluster assembly and blocked synthesis of heme. A late-onset pyridoxine-refractory sideroblastic anemia caused by homozygous mutation in GLRX5 has been described in a patient who in middle age developed symptoms of a microcytic hypochromic anemia, type 2 diabetes, cirrhosis, and liver iron overload. HSPA9 is a mitochondrial heat shock protein 70 homolog that is involved in transfer of iron-sulfur complexes to mitochondrial glutaredoxin 5. Mutations in HSPA9 cause nonsyndromic microcytic to normocytic sideroblastic anemias.

In addition to genetically defined forms of hereditary sideroblastic anemia, a number of syndromic types have been described, which present with anemia in combination with either muscle, neurologic, or pancreatic tissue involvement. The first of these disorders to be defined by molecular genetics, the Pearson syndrome, is a rare entity that manifests in early infancy with anemia and exocrine pancreatic dysfunction. The anemia is normocytic or macrocytic, reticulocyte counts are low, and variable degrees of neutropenia and thrombocytopenia are present. The bone marrow shows striking vacuolation and ring sideroblasts. Although usually fatal, milder forms of the anemia are consistent with survival into adult life. The syndrome, which is related to the Kearns-Sayre syndrome, results from deletions, mutations, or duplications of mitochondrial DNA, variably affecting multiple tissues of the body.

A second syndromic congenital sideroblastic anemia, X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A), is a rare mitochondrial disease caused by loss-of-function mutations in the ATP binding cassette transporter ABCB7. ABCB7 is localized to the inner mitochondrial membrane and has been proposed to function as an exporter of mitochondrial iron-sulfur clusters to the cytoplasm; however, a direct role in heme synthesis may arise through an interaction with FECH. Males affected with XLSA/A usually present in infancy with nonprogressive or slowly progressive ataxia and incoordination, which is accompanied by a mild to moderate hypochromic microcytic anemia and the presence of ring sideroblasts on bone mar row examination.

Mutations in the high-affinity thiamine transporter gene SLC19A2, located at 1q24.2, cause the thiamine-responsive megaloblastic anemia (TRMA) syndrome. TRMA has the unusual bone marrow feature of megaloblastic erythroid maturation with ring sideroblasts. TRMA presents with early-onset megaloblastic anemia, diabetes mellitus, and sensorineural deafness, which respond variably to thiamine treatment. Mutations in other mitochondrial respiratory protein genes, including MT-ATP6 and NDUFB11, present in early childhood with lactic acidosis, myopathies, and in the case of MT-ATP6, neurological abnormalities.

MLASA1 and MLASA2, are classically characterized by the triad of muscle weakness, lactic acidosis, and normo- to macrocytic anemia. Missense and nonsense mutations in the PUS1 gene coding for pseudouridine synthase-1 cause the rare autosomal recessive disease, myopathy, lactic acidosis, and sideroblastic anemia (MLASA1). Mitochondrial and cytoplasmic transfer RNAs (tRNAs) from affected patients lack tRNA pseudouridylation at sites normally modified by PUS1; however, the mechanism by which this affects oxidative phosphorylation and iron metabolism in skeletal muscle and bone marrow are yet to be elucidated. MLASA2 has an identical phenotype caused by a homozygous mutation in the mitochondrial tyrosyl-tRNA synthetase gene, YARS2. The homozygous mutation in YARS2, identified in three patients from two consanguineous Lebanese families, causes defective mitochondrial synthesis and, similar to mutations in PUS1, results in defective oxidative phosphorylation. MLASA1 and MLASA2 usually present with progressive exercise intolerance commencing in childhood followed by later development of sideroblastic anemia, basal lactic acidemia, and mitochondrial myopathy. A biallelic mutation has been described in another mitochondrial protein synthesis gene, LARS2, in a single patient with a related, lethal mitochondrial phenotype that included sideroblastic anemia.

Over a dozen mutations in the TRNT1 gene, which encodes an essential enzyme that transfers the CCA nucleotide repeat to tRNA molecules, result in sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). This autosomal recessive syndromic disorder manifests as a severe sideroblastic anemia in infancy, recurrent periodic fevers, B-cell lymphopenia, and hypogammaglobulinemia.

Acquired Sideroblastic Anemia

Acquired sideroblastic anemia is categorized within the myelodysplastic syndromes and may appear de novo or occur after chemotherapy or irradiation (see Table 1). The clonal nature of hemopoiesis in this condition was first suggested by Dacie et al.

The World Health Organization (WHO) Classification collectively groups myelodysplastic syndromes with ring sideroblasts as “MDS-RS” and distinguishes three categories: MDS with ring sideroblasts and single-lineage dysplasia (MDS-RS-SLD), MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN RS-T). Many patients with refractory anemia with ring sideroblasts and thrombocytosis have a point mutation in the Janus kinase 2 gene (changing valine-617 to phenylalanine), which is a feature usually associated with the myeloproliferative disorders. This latter group have a clinical phenotype that includes normal MCV, marrow fibrosis, and splenomegaly.

Biologic and Molecular Aspects

Clonal hematopoiesis has been demonstrated in acquired idiopathic sideroblastic anemia and in the related myelodysplastic syndromes. Specific evidence was first provided by finding a single G6PD isoenzyme in erythrocytes, granulocytes, platelets, and B lymphocytes in a woman who was heterozygous for G6PD and carried two isoenzymes in her skin and T lymphocytes. This technique is applicable only to the few women who have G6PD heterozygosity, but restriction fragment length polymorphism analysis can be applied to most women using probes directed at other X-chromosome genes, such as that for phosphoglycerate kinase or to an X-linked, variable-copy-number tan dem repeat sequence. The results show uniform monoclonality of hematopoiesis in acquired sideroblastic anemia with or without associated myelodysplastic features. Some indirect evidence exists for a primary mitochondrial lesion, perhaps in the mitochondrial respiratory chain, which impairs the reduction of Fe3+ because Fe2+ is essential for heme synthesis. Recurrent mutations in the SF3B1 gene have been described in acquired sideroblastic anemia and are found in 70% to 90% of patients with MDS-RS. The product of SF3B1 is associated with mRNA splicing, and mutations in this gene may influence a number of mitochondrial gene networks, including changes in the expression of the iron transporter ABCB7, resulting in iron-laden mitochondria during erythroid development. MDS-RS-T cases have somatic SF3B1 mutations and gain-of-function hematopoietic receptor tyrosine kinase–signaling mutations, most commonly JAK2 valine-617 to phenylalanine, and less commonly other JAK2, MPL, or CALR gene mutations. Genetic mutations in other spliceosome components, including SRSF2, ZRSR2, and PRPF8, are found in MDS-RS lacking SF3B1 mutations; however, it is unclear whether these variants play any pathogenic roles in disease development or progression.

Etiology

Clonal chromosomal changes are found in bone marrow cells in approximately 60% of patients with acquired sideroblastic anemia. Characteristic changes are monosomy 7; trisomy 8; deletions involving chromosomes 5, 7, 11, or 20; and a number of balanced translocations. When sideroblastic anemia is acquired after chemotherapy or irradiation, chromosomal changes are usually found and tend to be multiple. Among these changes, the loss of an entire chromosome (5 or 7, or both), deletion of a long arm [del(5), del(7), or del(13)], and an unbalanced translocation are typical. When karyotype shows loss of material from chromosomes 5 or 7, or both, a detailed occupational history may show exposure to potentially mutagenic chemical agents in a proportion of patients. However, the development of visible chromosomal changes is probably a late event in acquired sideroblastic anemia and may be preceded by the expansion of a clone of genetically unstable stem cells. This concept is in accord with the view that multiple genetic events underlie the pathogenesis of other myelodysplastic syndromes and acute myeloid leukemia.

Differential Diagnosis

 Ring sideroblasts are not limited to acquired sideroblastic anemia; they also occur in other myelodysplastic conditions, such as refractory anemia with excess blasts, in which the blast count is higher than 5%. Careful examination of peripheral blood and bone marrow can distinguish acquired idiopathic sideroblastic anemia from these related myelodysplastic conditions. Family surveys are very useful in distinguishing acquired from hereditary forms of sideroblastic anemia, because the latter may present in late adult life.

Prognosis

Using MDS prognostic models, MDS-RS has the most favor able outlook among the myelodysplastic syndromes. The Revised International Prognostic Scoring System (R-IPSS) uses the bone marrow blast percentage, karyotypic analysis, and the presence of peripheral blood cytopenias to group newly diagnosed cases into one of five prognostic groups. Very low-risk patients have a median survival of 8.8 years, low-risk patients 5.3 years, intermediate-risk patients 3 years, high-risk patients 1.6 years, and very high-risk patients 0.8 years. MDS-RS is generally stratified into low- risk groups. For example, in a Mayo Clinic cohort of 48 patients with MDS-RS-SLD using the R-IPSS, 34% were classified as very low, 64% as low, and 2% as intermediate. The median OS for patients with MDS-RS-SLD ranges from 69 to 108 months, with a very low risk for leukemic transformation ( <2 %). The survival of patients with MDS-RS-MLD is inferior to that of MDS RS-SLD, but better than that of patients with MDS-MLD. Karyotypic analysis of marrow aspirates provides valuable information, because a normal karyotype carries a more favorable prognosis. Conversely, chromosome 7 abnormalities impart a high probability of transformation to acute myeloid leukemia. Multiple chromosomal abnormalities and del(20q) are also associated with an increased risk for progression to leukemia; in contrast, trisomy 8 has no adverse prognostic significance.

اخر الاخبار

اخبار العتبة العباسية المقدسة

عبر مركز تراث كربلاء.. قسم شؤون المعارف ينجز مؤلفات تراثية ويستعد لإصدارات علمية جديدة

ملاكات قسم الشعائر تشارك في حملة التبرع لإغاثة الشعبين الإيراني واللبناني

قسم العلاقات العامة ينظم برنامجًا ثقافيًّا لوفد مؤسسة الغدير للمعاقين

المجمَع العلمي يكرّم 30 قارئًا شاركوا بإحياء الختمات القرآنية الرمضانية في الديوانية

المزيد

الآخبار الصحية

علاج طبيعي لمشكلات البشرة وحب الشباب

اكتشاف ارتباط عنصر شائع في نظامنا الغذائي بحصوات المرارة

كل ليلة.. 11 دقيقة إضافية من النوم لها مفعول السحر

علاج طبيعي يخفف أعراض سكري الحمل

المزيد

الآخبار التكنلوجية

قمر وردي ومذنب يلامس الشمس.. 8 ظواهر فلكية تزين السماء طوال شهر أبريل

تفسير حديث لتحيز التوحد بين الجنسين.. هل تمتلك الإناث "درعا جينيا" ضد المرض؟

الجلوس الذهني النشط.. مفتاح تقليل خطر الخرف لدى كبار السن

خسائر غير مسبوقة للجليد في أيسلندا وسواحل المحيط الهادئ خلال 2025

المزيد

مواضيع ذات صلة

Addison’s Disease

Cushing’s Disease

Osteoporosis

Pathophysiology of Beta-Thalassemia Syndromes

Etiology and Pathophysiology of Anemia of Chronic Inflammation

Goitre and Thyroid nodules

Pathogenesis of Cobalamin Deficiency

Clinical Manifestations of Iron Overload

Pathobiology of Acquired Iron Overload

Thyroid Disease in Pregnancy

Hypothyroidism

Hyperthyroidism