Causes and pathophysiology of the sideroblastic anemias

INTRODUCTION — 

The sideroblastic anemias are anemias defined by the presence of ring sideroblasts, which are erythroblasts containing iron encrusted mitochondria that appear to encircle the nucleus, in bone marrow aspirate smears stained with the Prussian blue iron stain.

Ring sideroblasts are found in diverse circumstances, encompassing a broad spectrum of both inherited and acquired causes (table 1). Understanding the underlying causes and mechanisms is useful for predicting the clinical course and guiding therapy, which differ for the various forms.

This topic review discusses congenital and acquired causes of sideroblastic anemias and their pathophysiology. The clinical presentations and diagnostic testing for specific forms of sideroblastic anemia, and an approach to patient management, are presented in detail separately. (See "Sideroblastic anemias: Diagnosis and management".)

CAUSES OF SIDEROBLASTIC ANEMIA — 

The conventional classification of the sideroblastic anemias is structured on whether the cause is congenital (inherited) or acquired, and further subclassified by genetic or environmental factors (table 1) [1,2]. In searching for the cause, it can also be helpful to note whether the anemia is microcytic or normocytic/macrocytic and whether there are other associated clinical anomalies or disorders (syndromic features) (table 2).

Congenital sideroblastic anemias — The congenital sideroblastic anemias (CSAs) are caused by germline pathogenic variants affecting a gene or genes encoded by nuclear or mitochondrial DNA. The underlying causes of many cases can be established at the molecular level, as illustrated in the diagram (figure 1), but approximately one-third of cases do not yet have an identifiable genetic cause [3-5]; this is the topic of ongoing research.

The CSAs can be subdivided into nonsyndromic and syndromic forms (table 1), by their mode of inheritance (X-linked, autosomal recessive, or mitochondrial) or according to red blood cell size (microcytic or normocytic-to-macrocytic) (table 2). The majority are nonsyndromic, with isolated anemia and ring sideroblasts in the bone marrow. The syndromic forms, which affect other organ systems, are relatively uncommon.

Nonsyndromic congenital sideroblastic anemias — Because of the frequency of certain diseases, notably X-linked sideroblastic anemia (XLSA), most patients have a nonsyndromic CSA. Pathogenic variants in six genes involved in heme synthesis or iron-sulfur cluster biogenesis cause nonsyndromic CSA.

X-linked sideroblastic anemia (XLSA; ALAS2 gene) — X-linked sideroblastic anemia (XLSA) was first described in the 1940s. In the 1990s, linkage to the ALAS2 locus, the erythroid-specific form of 5-aminolevulinate synthase (ALAS) was established in several kindreds [1]. ALAS catalyzes the first and rate-limiting step in heme synthesis: the condensation of glycine and succinyl-CoA to form 5-ALA (figure 2); ALAS2 is essential for erythroid development and survival of vertebrates [6,7]. (See 'Heme synthesis' below.)

ALAS2 is located on the X chromosome [8,9]. Although XLSA is most commonly seen in males, nearly one-third of affected individuals are females who are considered to manifest the disorder because they develop highly skewed X inactivation in hematopoietic cells, favoring expression of the mutant allele [10-13]. Females with XLSA often present later in life and have a normocytic or macrocytic anemia rather than microcytic anemia typical of the disease in males. (See "Sideroblastic anemias: Diagnosis and management", section on 'Diagnostic approach'.)

Over 100 distinct pathogenic variants in ALAS2 have been identified in more than 130 unrelated probands/families. Disease-causing variants are most often missense mutations that affect the catalytic domain of ALAS2 and reduce enzymatic function in vitro in many, but not all, cases [1,14]. Nonsense mutations, including premature stop codons and frameshifts, and variants altering ALAS2 splicing, mutations in a GATA1 transcription factor binding site in intron 1, and regulatory mutations in the ALAS2 promoter region are uncommon; null mutations are seen only in heterozygous females [1,14-17].

Autosomal recessive congenital sideroblastic anemia — .

●SLC25A38 – SLC25A38 encodes an erythroid-specific mitochondrial amino acid carrier that transports glycine into mitochondria; this is necessary for the first step in heme synthesis [18]. Multiple biallelic pathogenic variants in the SLC25A38 gene associated with microcytic congenital sideroblastic anemia have been identified in over 90 families [19]. Among the nonsyndromic CSAs, SLC25A38 sideroblastic anemia is the second most common after XLSA [19].

●HSPA9, HSCB, and GLRX5 – HSPA9, HSCB, and GLRX5 are each involved in the initial step of iron-sulfur (Fe-S) cluster synthesis in mitochondria. Fe-S clusters are prosthetic groups that are essential components of many mitochondrial and several cytosolic proteins, the former including succinyl dehydrogenase (SDH) and mitochondrial aconitase, and the latter including iron regulatory protein 1 (IRP1/cytosolic aconitase/ACO1) and ferrochelatase (FECH) [20].

HSPA9 is a nuclear gene that encodes a mitochondrial HSP70 homologue. Heterogeneous pathogenic variants have been discovered in 12 families or isolated cases [21,22]. Most patients have a rare null, splicing or occasionally missense allele in trans of a common synonymous coding variant that is thought to reduce splicing efficiency.

In one patient, biallelic pathogenic variants in HSCB, which encodes a co-chaperone of HSPA9, were reported [23].

GLRX5 encodes a glutaredoxin required for the initial assembly of the Fe-S cluster. Homozygous and heterozygous biallelic pathogenic variants in GLRX5 have been described in four patients [24-27]. The anemia in these CSAs is typically microcytic.

●FECH – FECH encodes ferrochelatase, the final enzyme in the heme synthetic pathway, which inserts an iron atom into protoporphyrin IX (figure 2). Pathogenic variants in FECH cause erythropoietic protoporphyria (EPP), in which patients develop acute, non-blistering cutaneous photosensitivity due to accumulation of excess free protoporphyrin. Many individuals with EPP have a mild microcytic anemia. Ring sideroblasts have been documented in 10 patients [28,29] and not found in others [30], but a systematic study of the frequency of ring sideroblasts in EPP has not been performed. EPP is discussed in detail separately. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

Syndromic congenital sideroblastic anemias — Syndromic CSAs have other, nonhematologic manifestations such as neuromuscular and metabolic abnormalities in addition to bone marrow ring sideroblasts, and they are often named in a manner that describes the syndromic collection of phenotypes, rather than by specific genes, as some syndromes have multiple underlying genetic causes (table 1 and table 2).

X-linked sideroblastic anemia with ataxia (XLSA/A; ABCB7 gene) — X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare congenital sideroblastic anemia, characterized by relatively mild anemia and a clinically more significant, non-progressive spinocerebellar ataxia [31]. XLSA/A is due to pathogenic variants in the ABCB7 gene, which is located on the X chromosome, and encodes an essential transporter localized to the inner mitochondrial membrane [32]. This transporter is thought to be involved in the transfer of Fe-S clusters into the cytoplasm for assembly of cytoplasmic Fe-S cluster-containing proteins [33]. Several variants have been described that cause partial loss of function of the transporter protein [33-36]. (See 'Iron-sulfur (Fe-S) cluster biogenesis' below.)

Myopathy, lactic acidosis, and sideroblastic anemia (MLASA; IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2 genes) — MLASA was first defined as an autosomal recessive oxidative phosphorylation disorder in 2004; the phenotype was characterized by progressive exercise intolerance during childhood, onset of sideroblastic anemia usually around adolescence, lactic acidemia, and mitochondrial myopathy and caused by biallelic pathogenic variants in PUS1, which encodes pseudouridine synthase 1 [37,38].

Subsequently, the MLASA syndrome was described in individuals with biallelic pathogenic variants in other genes, namely:

●Genes that encode mitochondrial tRNA synthetases (IARS2, LARS2, SARS2, YARS2) [39-44]

●MT-ATP6, a mitochondrial gene that encodes an ATP-synthase (Complex V) subunit [45,46]

●NDUFB1, an X-linked subunit of complex I [47,48]

Phenotypes are partially overlapping with variable degrees of severity. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Predominantly multisystem disease with myopathy'.)

The roles of these proteins in mitochondrial protein synthesis are discussed below. (See 'Mitochondrial protein synthesis' below.)

Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (SIFD, pathogenic variants in TRNT1) — Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is a syndromic microcytic sideroblastic anemia, characteristically, but not always, associated with a B cell lymphopenia, panhypogammaglobulinemia, periodic fevers and developmental delay, with onset in infancy [49,50]. Neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem derangements are variably present. Subsequent case studies have expanded the spectrum of clinical features even further, to include milder phenotypes such as isolated anemia or immunodeficiency, or nonsyndromic retinitis pigmentosa with microcytic red blood cells [51,52]. Early death in these patients is commonly due to cardiac or multiorgan failure. This syndrome and the management of its inflammatory component are discussed separately. (See "Autoinflammatory diseases mediated by miscellaneous mechanisms", section on 'SIFD syndrome'.)

SIFD is caused by biallelic pathogenic variants in TRNT1 [50]; this gene encodes the essential enzyme tRNA nucleotidyl transferase (also called CCA-adding enzyme) that adds CCA to the end of all nuclear and mitochondrial transfer RNAs before they can participate in polypeptide assembly on ribosomes. Transmission is autosomal recessive, and parental consanguinity is commonly present [49-52]. (See 'Mitochondrial protein synthesis' below.)

Pearson syndrome (mitochondrial DNA deletions, duplications and other rearrangements) — Pearson syndrome (Pearson marrow pancreas syndrome, PMPS) is a congenital multisystem disorder characterized by severe sideroblastic anemia, milder neutropenia and thrombocytopenia, pancreatic insufficiency, lactic acidosis, and failure to thrive from infancy or early childhood. New observations have broadened the phenotypic spectrum of the syndrome to include patients with onset later than previously reported, as well as individuals with principally bone marrow findings [53]. Consequently, there may be atypical disease presentations that cause the diagnosis to be overlooked or misattributed to other conditions. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Pearson syndrome' and "Shwachman-Diamond syndrome", section on 'Differential diagnosis' and "Overview of the causes of chronic diarrhea in children in resource-abundant settings", section on 'Pancreatic exocrine insufficiency'.)

The syndrome is caused by large deletions or rearrangements of mitochondrial DNA, resulting in the loss of multiple proteins and/or transfer RNAs encoded by the mitochondrial genome [54]. These major molecular defects are associated with pronounced abnormalities in the ultrastructure of erythroblast mitochondria [55]. (See 'Disrupted mitochondrial pathways in erythroid precursors' below.)

Thiamine-responsive megaloblastic anemia (pathogenic variants in SLC19A2) — Thiamine-responsive megaloblastic anemia (TRMA, also called Rogers syndrome) is characterized by megaloblastic anemia, type I diabetes mellitus, and sensorineural deafness that typically manifests between infancy and adolescence [56]. Hematologic findings may also include variable degrees of neutropenia and thrombocytopenia. Diverse other features are reported, including stroke-like episodes and optic atrophy. (See "Macrocytosis/Macrocytic anemia", section on 'Megaloblastic anemia'.)

TRMA is caused by biallelic variants in the SLC19A2 gene, which encodes a high-affinity thiamine transporter, with diverse variants identified in many kindreds [56-59].

Acquired sideroblastic anemias — Acquired sideroblastic anemias are subdivided into the clonal forms (myelodysplastic syndromes with ring sideroblasts [MDS-RS]) and the forms due to an environmental exposure or deficiency that affects aspects of erythroblast iron handling (table 1). In the latter, such as those due to chronic ethanol consumption, certain drugs, copper deficiency, and hypothermia, the sideroblastic anemia resolves when the cause is corrected. Most of the acquired sideroblastic anemias are normocytic or macrocytic (table 2). Certain forms, such as those due to isoniazid and sometimes ethanol, are microcytic. (See 'Medications' below and 'Alcohol' below.)

Excessive alcohol may also cause macrocytosis. (See "Hematologic complications of alcohol use", section on 'Anemia'.)

Clonal (MDS/MPN subtypes) — Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders, typically acquired in adulthood. They are characterized by dysplastic maturation and ineffective production of erythrocytes. Ring sideroblasts are present in the following MDS or MDS/MPN variants [60]:

●MDS-RS-SLD – MDS with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD)

●MDS-RS-MLD – MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD)

●MDS/MPN-RS-T – MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)

There is a very close association between MDS/MPN variants with ring sideroblasts and specific somatic mutations in genes implicated in mRNA splicing, suggesting a causal relationship.

Principal among them is the SF3B1 gene, which encodes the spliceosome component SF3B1 (splicing factor 3B, subunit 1), is mutated in 70 to 90 percent of cases of MDS with ring sideroblasts and only infrequently in MDS without ring sideroblasts [61-64]. A pharmacologic inhibitor of SF3B splicing function was found to induce ring sideroblasts in human cells, also supporting a causative role of the mutations in the ring sideroblast abnormality [65]. (See 'Pathophysiology' below.)

Some cases of the MDS/MPN subtypes have been associated with other acquired genetic defects including loss of a FECH allele, JAK2 mutation, mitochondrial DNA mutation, and other alterations affecting the RNA splicing machinery [62,63,66,67]. The genetic changes in MDS are discussed in more detail separately. (See "Cytogenetics, molecular genetics, and pathophysiology of myelodysplastic syndromes/neoplasms (MDS)".)

Reversible — The defining feature of the acquired sideroblastic anemias other than MDS/MPN is the reversibility following correction of the underlying abnormality, if it can be identified.

Alcohol — A sideroblast phenotype is but one of many features contributing to the anemia associated with excess alcohol use. In a study involving 121 individuals with chronic alcohol use and anemia, ring sideroblasts were documented in 23 percent, but were always accompanied by at least one other abnormality such as folic acid deficiency or malnutrition [68]. (See "Hematologic complications of alcohol use".)

Medications — Certain medications have been found to produce sideroblastic anemia. Classic examples include the anti-tuberculosis drug isoniazid and the antibiotics chloramphenicol and linezolid.

●Isoniazid (INH) – While INH has been extensively used to treat tuberculosis for over seven decades, sideroblastic anemia associated with its use has been documented in only a few dozen case studies. The apparent low incidence has been attributed at least in part to the routine co-administration of pyridoxine (vitamin B6) to prevent INH-induced neuropathy (see "Isoniazid: An overview", section on 'Dosing and administration'). It has also been suggested that an occult hematologic abnormality in some individuals may make them more susceptible. Strong evidence that the related drugs pyrazinamide and cycloserine cause sideroblastic anemia is lacking.

INH interference with pyridoxine metabolism, and thus with the function of ALAS2, is considered to be the basis for sideroblastic anemia. The anemia is reversed by discontinuing the INH or by pyridoxine supplementation. (See 'Heme synthesis' below.)

●Chloramphenicol and linezolid – Chloramphenicol was well documented to cause a sideroblastic anemia in a dose-dependent manner in the past [69]. The association of sideroblastic anemia with linezolid use was described more recently [70-72]. Both of these drugs inhibit mitochondrial protein synthesis. (See 'Mitochondrial protein synthesis' below.)

●Other medications – A number of other drugs have been implicated in causing sideroblastic anemia in a few cases. (See "Sideroblastic anemias: Diagnosis and management", section on 'Medications'.)

Hypothermia — Ring sideroblasts have been described in three patients with episodic hypothermia [73]. The cause is thought to involve the known sensitivity of certain mitochondrial functions to reduced temperature; these functions include translocation of proteins into mitochondria, heme synthesis, and iron incorporation into hemoglobin [1].

Copper deficiency — Copper deficiency can cause sideroblastic anemia, often with neutropenia, and is commonly accompanied by diverse neurologic deficits. There are several settings in which copper deficiency can develop, including small bowel disorders, bariatric surgery, prolonged enteral or parenteral nutrition without copper supplementation, use of the chelating agent trientine (triethylene tetramine dihydrochloride; TTH), and excess zinc ingestion, the latter often occurring from common sources that often are not considered such as denture adhesives and over the counter homeopathic remedies. (See "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency'.)

Transient sideroblastic anemia during pregnancy — Several reports have described sideroblastic anemia manifesting during pregnancy, in successive pregnancies or postpartum [74,75]. Molecular analysis for a hereditary cause was not performed in these cases.

Vitamin B6 stores can be reduced during pregnancy, and, in one instance, a low vitamin B6 level was documented and supplements increased the Hb level [74]. However, comprehensive data are lacking on nutritional sufficiency of vitamin B6 during pregnancy. (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Vitamin B6'.)

PATHOPHYSIOLOGY — 

Sideroblastic anemia is due to impaired maturation and death of developing erythroid cells (referred to as ineffective erythropoiesis) and an erythroid hyperplasia that is further exacerbated by the effects of anemia-associated hypoxia on erythropoietin production. Ineffective erythropoiesis induces changes in iron metabolism, increasing iron absorption and eventually causing systemic iron overload that may have its own morbidity. (See 'Iron overload' below and "Sideroblastic anemias: Diagnosis and management", section on 'Laboratory and bone marrow findings'.)

Disrupted mitochondrial pathways in erythroid precursors — Mitochondria in developing erythroid cells play a central role in the pathogenesis of all sideroblastic anemias (figure 1) as they are the cellular site of heme production and iron utilization. Primary defects in components of iron trafficking pathways are not known to be involved in the pathogenesis of the sideroblastic anemias. Rather, each known cause that leads to a sideroblastic anemia disrupts one or more of four mitochondrial metabolic pathways [2,76]:

●Heme synthesis

●Iron sulfur-cluster biogenesis or transport

●Mitochondrial protein synthesis

●Oxidative phosphorylation

In sideroblastic anemias, iron is delivered to erythroblast mitochondria normally [77,78]. However, the disrupted mitochondrial pathway(s) blocks the iron utilization that occurs exclusively in mitochondria. Feedback mechanisms to reduce iron import into mitochondria are not known to exist, and, if they do exist, they are overwhelmed by the metabolic abnormalities. Consequently, iron accumulates in the mitochondrial matrix, where it is incorporated into mitochondrial ferritin [79,80]. The diagnostic ring sideroblast is detected by staining the bone marrow aspirate smear with the Prussian blue (Perls) iron stain, wherein erythroblasts contain numerous coarse blue "granules" that characteristically appear to encircle or form a ring around the nucleus (picture 1). Ultrastructurally, the granules are due to pathological, amorphous electron dense (dark) mitochondrial deposits (picture 1).

Heme synthesis — Although heme synthesis occurs in all nucleated cells, developing red blood cells (RBCs) have the greatest heme requirement of any cell type. Hemoglobin contains nearly 80 percent of the body heme and therein more than two-thirds of the body iron. The heme biosynthesis pathway involves a sequential assembly of the porphyrin ring from glycine and succinyl-coenzyme A (CoA) and also the concerted shuttling of intermediates from mitochondria to cytosol and back again, with heme ultimately being formed by insertion of ferrous iron into protoporphyrin IX (figure 2).

Exceptionally robust erythroid heme production is made possible by the expression of an erythroid-specific form of 5-aminolevulinate (ALA) synthase (ALAS2), as well as the presence of erythroid-specific promoters in the genes encoding several other enzymes in the heme synthesis pathway [1]. The transcription of these mRNAs is mediated by erythroid-specific factors, like many other genes that are differentially regulated in erythroid cells. In addition, translational regulation is important for ALAS2 expression; this occurs via interaction of the iron regulatory protein 1 (IRP1) with the ALAS2 mRNA, linking ALAS2 translation with iron availability in the cell [81].

Inherited disorders — Pathogenic variants affecting proteins that are integral to erythroid heme synthesis lead to reduced heme production and microcytic RBCs (similar to iron-deficiency anemia ) in three forms of microcytic congenital sideroblastic anemia:

●X-linked sideroblastic anemia – X-linked sideroblastic anemia (XLSA) is due to pathogenic variants in the ALAS2 gene, which is located on the X chromosome and encodes the first and rate-limiting enzyme of the heme synthesis pathway. The severity of anemia is highly variable and can be related to the location of the altered amino acid within the ALAS2 enzyme, thereby determining its impact on the enzyme's function [14,82,83]. Despite the X-linked inheritance pattern, and in contrast to most X-linked disorders, about one-third of affected individuals are female [1]. This high rate of disease expression in females is considered to be due to highly skewed X chromosome inactivation of the wild-type allele, which occurs in hematopoietic tissue with advancing age. (See "Genetics: Glossary of terms", section on 'X-inactivation'.)

Pathogenic variants in ALAS2 seen in females tend to be more damaging to the enzyme; they often cause severe disease and can be lethal in males [1,11]. In exceptional cases, there may be "constitutional" skewing of X chromosome inactivation that causes the disease to manifest in females earlier in life [10]. The mechanism of XLSA in a first reported female fetus is unclear [84]. (See 'X-linked sideroblastic anemia (XLSA; ALAS2 gene)' above.)

Pyridoxine (vitamin B6) is converted in the liver to the active co-enzyme pyridoxal-5’-phosphate, the cofactor for ALAS. In up to two-thirds of male patients with XLSA, and in rare female patients, the anemia responds to pyridoxine supplements (to a variable extent) by enhancing the function of some ALAS2 mutant proteins, in particular when the mutations affect pyridoxal-5’-phosphate binding to the ALAS enzyme [82].

Two cases illustrate this phenomenon:

•A patient with a de novo missense mutation in exon 5 of ALAS2, located within the catalytic domain of the enzyme, had reduced activity of the enzyme expressed in vitro (15 percent of normal) that was increased to 34 percent by the addition of pyridoxal-5’-phosphate; this correlated with clinical improvement upon vitamin B6 administration [85].

•A familial missense mutation in exon 8 of ALAS2, located near the pyridoxal-5’-phosphate binding site was associated with bone marrow ALAS2 activity of approximately 30 percent when the index patient was not taking vitamin B6; ALAS2 enzymatic activity as well as the hemoglobin level was restored to normal upon vitamin B6 administration [86].

●Mitochondrial transporter SLC25A38 deficiency – The erythroid-specific carrier protein SLC25A38 imports glycine across the inner mitochondrial membrane. Although there are pathways that synthesize glycine within mitochondria, this is consequential because of the extreme glycine demand for heme synthesis in the erythroblast (each heme molecule incorporates 8 glycines) and because ALAS has a very low affinity for glycine, so that large amounts of glycine are required as a substrate for ALAS [18,87].

Biallelic variants in SLC25A38 are associated with severe, transfusion-dependent anemia that generally presents in infancy [19]. Many of the variants cause complete loss-of-function of the carrier protein. (See 'Autosomal recessive congenital sideroblastic anemia' above.)

●Ferrochelatase deficiency – Ferrochelatase (FECH) catalyzes the final step in heme syntheses. Incomplete deficiency of FECH is due to a group of diverse pathogenic variants affecting the FECH enzyme and causes the autosomal recessively (or "pseudo-dominantly") inherited erythropoietic protoporphyria (EPP). EPP is manifested in erythroid cells by marked accumulation of metal-free protoporphyrin during the final stages of erythroblast maturation, when defective FECH becomes rate-limiting for heme production. Most patients have mild microcytic anemia. Although the presence of ring sideroblasts was only documented in 10 cases (and not found in others), iron accumulation in erythroblast mitochondria would be expected in the setting of FECH deficiency [28-30]. Ring sideroblasts may occur variably as iron uptake appears to be restricted to match the FECH deficiency [88]. (See 'Nonsyndromic congenital sideroblastic anemias' above.)

Acquired states — Reduced erythroid heme synthesis can be acquired, causing reversible sideroblastic anemia. (See 'Reversible' above.)

●Isoniazid (INH) – INH is an antituberculosis agent that interferes with pyridoxine metabolism and the function of ALAS2, in turn impairing heme synthesis via two apparent mechanisms (see 'Medications' above):

•As a vitamin B6 antagonist, INH forms hydrazones with pyridoxal-5’-phosphate that inhibit pyridoxal phosphokinase, thus impairing the conversion of pyridoxine to its active cofactor form pyridoxal-5’-phosphate and depleting pyridoxal-5’-phosphate levels [69].

•INH inhibits the ALAS2 enzyme directly, although this has not been ascertained in human erythroblasts [89].

●Excess alcohol – Ring sideroblasts and microcytic, hypochromic anemia observed with chronic alcohol use has been attributed to impairment of heme synthesis through the effect of alcohol on vitamin B6 metabolism as well as on subsequent steps of heme synthesis [69,90]. Toxic effects on mitochondrial protein synthesis are likely also involved and are caused by ethanol, acetaldehyde, or both. (See 'Alcohol' above.)

Iron-sulfur (Fe-S) cluster biogenesis — Iron imported into mitochondria of erythroid cells is also required to generate Fe-S clusters. Fe-S clusters are essential prosthetic groups in numerous proteins, including those regulating cellular iron uptake, heme synthesis, and iron storage, such as iron regulatory protein 1 (IRP1) and FECH [91]. Fe-S clusters are synthesized exclusively in mitochondria via a multistep process and are then incorporated into mitochondrial as well as cytoplasmic recipient proteins [91].

Four forms of sideroblastic anemia provide examples of impaired Fe-S cluster generation that secondarily impacts heme synthesis and results in microcytic RBCs.

●HSPA9, HSCB, and GLRX5 deficiencies – HSPA9 and its co-chaperone HSCB are involved in mitochondrial Fe-S cluster assembly and transfer of nascent Fe-S clusters to glutaredoxin 5 for their transport to target proteins [2]. All three deficiencies (HSPA9, HSCB, and GLRX5) are autosomal recessive. However, in many cases, a severe HSPA9 loss-of-function allele is associated with a common variant that leads to reduced protein expression on the other HSPA9 allele, resulting in a pseudodominant inheritance pattern [21].

In addition to altering the function of the numerous mitochondrial Fe-S proteins, HSPA9, HSCB, and GLRX5 deficiencies are also presumed to repress ALAS2 translation in an iron regulatory protein 1-dependent manner; Fe-S deficiency activates IRP1 to its RNA binding form, leading to repression of ALAS2 translation and impaired heme synthesis [20]. (See 'Autosomal recessive congenital sideroblastic anemia' above.)

●X-linked sideroblastic anemia with ataxia (XLSA/A) – ABCB7 is a mitochondrial transporter that transfers Fe-S clusters or a mitochondrial component required for the cytosolic Fe-S cluster assembly machinery to the cytosol [33,91]. Pathogenic variants in ABCB7 are associated with XLSA/A. In cell culture models, knockdown of ABCB7 leads to loss of mitochondrial and cytosolic Fe-S proteins, defective heme biosynthesis via repression of ALAS2 and decreased stability of FECH as well as mitochondrial iron overload, triggering apoptosis of erythroid precursors, similar to GLRX5 deficiency [92]. (See 'X-linked sideroblastic anemia with ataxia (XLSA/A; ABCB7 gene)' above.)

The pathogenesis of the associated neurologic manifestations is unclear, but these manifestations are associated with cerebellar hypoplasia. As in Friedreich ataxia, which is due to a deficiency early in Fe-S cluster biogenesis, selectively disrupted Fe-S cluster and mitochondrial iron homeostasis in neural cells may be involved. (See "Friedreich ataxia", section on 'Pathogenesis'.)

Mitochondrial protein synthesis — Sideroblastic anemias with multisystem syndromic manifestations are typically associated with a diverse group of gene variants involving mitochondrial proteins that are unrelated to heme synthesis and Fe-S protein production. While most proteins (>1000) necessary for mitochondrial function are encoded by the nuclear genome and imported into the mitochondrion, there are 13 proteins encoded by the mitochondrial genome, which is maternally inherited; these proteins represent components of respiratory chain complexes. For their translation, the mitochondrial genome also encodes 12 mitochondrial transfer RNAs (tRNAs) and 2 mitochondrial ribosomal RNAs [93]. This dual genetic contribution to the mitochondrial proteome adds to the difficulty in the interpretation of pathological findings and phenotypic features of these syndromes.

How these mitochondrial protein synthesis deficiencies are linked to mitochondrial iron pathways or homeostasis leading to erythroblast mitochondrial iron overload and anemia remains elusive. Cellular hemoglobin production does not appear to be directly affected, as the erythrocytes are well-hemoglobinized and normocytic or macrocytic in most cases. The recurrent involvement of components of the mitochondrial respiratory chain in these syndromes may in part affect iron utilization in the erythroid cell, but the mechanism(s) is not understood [94]. Apart from mitochondrial heteroplasmy, the clinical features of the mitochondrial cytopathies are further obscured by the lack of an explanation as to why specific pathogenic variants affect some tissues but not others.

The pathogenesis of seven syndromes involves components of the mitochondrial protein translation apparatus that often impacts complexes of the respiratory chain. (See 'Syndromic congenital sideroblastic anemias' above.)

●Heteroplasmy of large deletions, rearrangements, or duplications of mitochondrial DNA (Pearson syndrome) – These usually sporadic aberrations lead to the loss of multiple proteins encoded by the mitochondrial genome in Pearson syndrome. Approximately one-half of cases have a 4977 base pair deletion that involves mitochondrially encoded subunits of respiratory complexes I, IV, and V, as well as several mitochondrial tRNA genes. The heteroplasmic nature of mitochondrial DNA at the cellular and organ levels is thought to account for the high variability of tissues affected over time in this condition. (See 'Pearson syndrome (mitochondrial DNA deletions, duplications and other rearrangements)' above.)

●PUS1 pathogenic variants – Pathogenic variants in PUS1, which encodes pseudouridine synthase, impair pseudo-uridylation of uridine, which has been implicated in the molecular pathogenesis by causing destabilization of tRNA structures and impaired mitochondrial protein translation [95]. In a study using induced pluripotent stem cells (iPSCs) derived from a patient with a homozygous PUS1 variant, as well as in a murine model harboring the same variant, it was demonstrated that PUS1 loss impairs mitochondrial function (protein synthesis, oxidative phosphorylation) and blocks erythroid differentiation [96]. In addition, the mammalian target-of-rapamycin (mTOR) pathway was activated in both the murine and human PUS1-deficient cells, and mTOR inhibition with rapamycin improved erythroid differentiation in both models. Moreover, rapamycin (sirolimus) treatment resulted in a sustained improvement in the patient's anemia. Further studies are awaited for confirmation of safety and efficacy of mTOR inhibition as treatment of PUS1-deficient anemia. (See 'Myopathy, lactic acidosis, and sideroblastic anemia (MLASA; IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2 genes)' above.)

●YARS2 pathogenic variants – YARS2 encodes mitochondrial tyrosyl-tRNA synthetase, which attaches tyrosine to its cognate mitochondrial tRNA (mt-tRNA). Pathogenic variants in YARS2 reduce levels of the enzyme and affect production of respiratory complex proteins encoded by the mitochondrial genome [40]. The high degree of variability in phenotype seen among siblings as well as in the same patient over time remains unexplained. (See 'Myopathy, lactic acidosis, and sideroblastic anemia (MLASA; IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2 genes)' above.)

●LARS2 pathogenic variants – LARS2 encodes mitochondrial leucyl-tRNA synthetase, which attaches leucine to its cognate mt-tRNA. Biallelic pathogenic variants in LARS2 reduced enzyme activity and complex I protein levels, resulting in multisystem failure in one reported patient [39]. (See 'Myopathy, lactic acidosis, and sideroblastic anemia (MLASA; IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2 genes)' above.)

●IARS2 pathogenic variants – IARS2 encodes mitochondrial isoleucyl-tRNA synthetase, which attaches isoleucine to its cognate mt-tRNA. In addition to previously described pathogenic variants in the IARS2 gene causing a range of overlapping clinical phenotypes in 18 patients, new variants have been added that were associated with neonatal sideroblastic anemia mimicking Pearson syndrome in three unrelated siblings [43]. Respiratory chain deficiency affecting erythropoiesis is implicated. (See 'Myopathy, lactic acidosis, and sideroblastic anemia (MLASA; IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2 genes)' above.)

●SARS2 pathogenic variants – SARS2 encodes mitochondrial seryl-tRNA synthetase, which attaches serine to its cognate mt-tRNA. Pathogenic variants in the SARS2 gene, previously found in hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis (HUPRA) syndrome or spastic paresis, were associated with sideroblastic anemia in a child who also co-inherited a spectrin abnormality causing hereditary spherocytosis [44]. In vitro culture studies of his CD34-positive cells showed markedly decreased cell proliferation, delayed erythroid maturation, and increased apoptosis; respiratory chain abnormalities were not found. (See 'Myopathy, lactic acidosis, and sideroblastic anemia (MLASA; IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2 genes)' above.)

●TRNT1 variants – TRNT1 encodes tRNA nucleotidyl transferase, which is essential for modifying all cytosolic and mitochondrial precursor tRNAs by adding the trinucleotide CCA to their 3' end. This modification is globally important for protein synthesis. Pathogenic variants in TRNT1 lead to metabolic dysfunctions in multiple organ systems, but their pathogenesis is not defined. (See 'Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (SIFD, pathogenic variants in TRNT1)' above.)

At the cellular level, formation of respiratory chain complexes was impaired in patient-derived fibroblasts [97]. Dysfunctional TRNT1 proteins may be unstable and/or their CCA-adding catalytic activity may be affected [51]. The wide clinical spectrum of the disorder is attributed to genetic heterogeneity, resulting in dysregulated tRNA maturation and abundance with effects on translation of distinct proteins [51,98].

TRNT1 deficiency is distinctive among the congenital sideroblastic anemias with defective protein synthesis insofar as it is uniformly markedly microcytic. This is almost certainly due to defective synthesis of extramitochondrial proteins such as hemoglobins.

Reversible inhibition of mitochondrial protein synthesis — Two antibiotics, chloramphenicol and linezolid, which cause the ring sideroblast anemia phenotype, interfere with mitochondrial protein synthesis at the level of mRNA translation [99]. Impaired heme synthesis, evident in reduced FECH activity, appears to be a secondary effect [90]. (See 'Medications' above.)

Oxidative phosphorylation — Exceptionally, pathogenic variants in the genes for two proteins of the respiratory chain themselves are associated with sideroblastic anemia:

●NDUFB11 – A recurrent pathogenic variant affecting the respiratory complex I-associated protein NDUFB11, which is encoded on the X chromosome, results in respiratory complex insufficiency and complex I instability. Impaired erythroid proliferation appears to be involved in the mechanism of the anemia [47,48]. (See 'Myopathy, lactic acidosis, and sideroblastic anemia (MLASA; IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2 genes)' above.)

●ATPase 6 – A recurrent heteroplasmic variant affecting the mitochondrial DNA-encoded ATPase 6 subunit of complex V (ATP synthase) is associated with variable mitochondrial respiratory impairment, which has not been further characterized [45,46]. Varying degrees of heteroplasmy correlate with variable clinical manifestations.

Sideroblastic anemias with incompletely understood pathogenesis — In three forms of sideroblastic anemia, the pathophysiology is less clear.

●MDS/MPN variants with ring sideroblasts – Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) arise from acquired mutations in a hematopoietic progenitor cell, leading to overgrowth of a mutant clone with variable disruption of the normal maturation of the cell lineages. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)" and "Overview of the myeloproliferative neoplasms".)

In the MDS/MPN variants with ring sideroblasts, impaired heme synthesis has long been indicated by two consistent features: a hypochromic population of RBCs and an increased erythrocyte protoporphyrin level [1]. However, genetic changes impacting heme synthesis such as FECH deficiency or mutated cytochrome c oxidase were only found in some cases.

The focus of research into the pathogenesis of these sideroblastic anemias has shifted to understanding the functional consequences of the commonly mutated SF3B1 mentioned above. (See 'Clonal (MDS/MPN subtypes)' above.)

Deregulation of genes implicated in congenital sideroblastic anemias has been found in gene expression studies. In erythroid precursor cells from patients with MDS/MPN variants with ring sideroblasts and SF3B1 mutations, ALAS2, HSPA9, GLRX5, and SLC25A37 are variably upregulated [100,101]. However, ABCB7 transcript abundance is reduced and has emerged as a leading candidate gene involved in causing the ring sideroblast abnormality [100,102,103]. Further, the aberrant splicing caused by mutant SF3B1 produces a premature termination codon in the ABCB7 mRNA, resulting in nonsense-mediated mRNA decay [104].

Experimental proof of SF3B1 pathogenic variants underlying ring sideroblast production has been obtained in two in vitro models of induced pluripotent stem cells (iPSC) and HUDEP (human umbilical cord blood-derived erythroid progenitor)-2 cells derived from individuals with SF3B1-mutant MDS, with efficient ring sideroblast formation during in vitro erythroid differentiation [105,106]. Reduced protein expression of mis-spliced ABCB7 and TMEM14C (a putative importer of protoporphyrinogen IX) and reversal of the ring sideroblast formation by functional rescue demonstrated that mis-spliced ABCB7 and TMEM14C cause SF3B1 mutant MDS [105].

Downstream, ABCB7 deficiency would cause impaired production of Fe-S cluster-containing proteins in the cytoplasm and thus indirectly affect heme synthesis as in XLSA/A. (See 'X-linked sideroblastic anemia with ataxia (XLSA/A; ABCB7 gene)' above and 'Autosomal recessive congenital sideroblastic anemia' above.)

●Thiamine-responsive megaloblastic anemia (TRMA) – The syndrome of megaloblastic anemia, non-type I diabetes mellitus and sensorineural deafness arises from biallelic pathogenic variants in a high-affinity thiamine transporter, SLC19A2. (See 'Thiamine-responsive megaloblastic anemia (pathogenic variants in SLC19A2)' above.)

The pathophysiology of this syndrome is unclear; multiple pathways appear to be involved. The megaloblastic anemia in TRMA is thought to result from defective nucleic acid synthesis attributed to cellular thiamine deficiency [107]; ring sideroblasts may be related to the role of thiamine in the production of succinyl-coenzyme A, a substrate of ALAS [108]. In that several thiamine-dependent enzymes involved in carbohydrate metabolism require the cofactor lipoic acid, production of which is mediated by the iron-sulfur containing enzyme lipoic acid synthetase, there may also be a link between thiamine metabolism and iron-sulfur cluster generation [2].

●Sideroblastic anemia associated with copper deficiency – Deficiency of copper normally does not occur in humans because of its adequate content in food. However, as mentioned above, nutritional copper deficiency is encountered in certain clinical settings as well as after excess ingestion of zinc. In these settings, copper deficiency typically leads to sideroblastic anemia, neutropenia, and neurologic deficits. (See 'Copper deficiency' above.)

The copper deficiency associated with excess zinc ingestion occurs because zinc induces an increase in the intestinal metal-binding protein metallothionein. Metallothionein preferentially binds copper in the gut and prevents its absorption, thereby enhancing its excretion in sloughed intestinal cells and leading to clinical copper deficiency [109]. The anemia is typically normocytic or slightly macrocytic, but its pathogenesis has not been elucidated in humans.

In classic studies of copper deficiency in experimental animals, in which the anemia is microcytic and hypochromic, heme synthesis in reticulocytes was not impaired. However, heme synthesis from ferric iron and protoporphyrin was decreased, suggesting that defective reduction of ferric iron to ferrous iron is linked to the observed diminished levels of the copper-containing enzyme cytochrome oxidase [110]. Moreover, intestinal absorption and mobilization of iron from macrophages and hepatocytes to transferrin was impaired because of the associated lack of the ferroxidase ceruloplasmin, which would limit the supply of iron to the bone marrow and contribute to the RBC microcytosis.

It remains unclear why the acquired copper deficiency targets the hematopoietic and nervous systems with clinical consequences. With copper depletion, the essential role of the metal for the integrity of mitochondrial metabolism may be compromised in a tissue-specific manner. In one study it was found that copper depletion impairs differentiation of cord blood-derived hematopoietic progenitor cells, which may relate to the normocytic anemia, neutropenia, and sometimes observed thrombocytopenia in patients with copper deficiency [111].

Ineffective erythropoiesis and iron overload — Ineffective erythropoiesis is a clinically significant feature of three common forms of sideroblastic anemia: those caused by defects in ALAS2 (XLSA), SLC25A38, and in acquired clonal MDS/MPN with ring sideroblasts. The ineffective erythropoiesis leads to increased intestinal iron absorption and consequent systemic iron overload.

Ineffective erythropoiesis — Certain anemias are associated with ineffective erythropoiesis, in which the underlying defect renders RBC precursors unable to complete maturation and causes them to die prematurely within the bone marrow. This process is also called intramedullary hemolysis (to distinguish it from hemolysis within the circulation). In sideroblastic anemias with defective heme synthesis, impaired hemoglobin production disrupts erythroblast maturation and the faulty erythroblasts are destroyed via mechanisms such as apoptosis, similar to the thalassemias [112-114]. Ineffective erythropoiesis is recognized morphologically by the disparate combination of intense erythroid hyperplasia in the bone marrow (due to anemia-induced increases in erythropoietin) and the absence of a reticulocytosis in the peripheral blood. Kinetically, an increased plasma iron turnover rate and a reduced incorporation of iron into circulating RBCs is demonstrated.

Iron overload — Ineffective erythropoiesis results in inappropriately increased intestinal iron absorption via suppression of the erythroid iron regulatory hormone hepcidin, which is mediated by erythroferrone (ERFE) produced by the expanded but ineffective erythron in the bone marrow [115]. This mechanism is reflected in low hepcidin and high circulating ERFE levels. Moreover, a variant ERFE is present in MDS with ring sideroblasts and pathogenic variants in SF3B1 [116]. Concentrations of circulating ERFE are higher in such patients, implicating that the variant ERFE in particular contributes to the iron overload in clonal acquired sideroblastic anemias [116].

The iron overload is indistinguishable from that of hereditary hemochromatosis, both clinically and on liver biopsy (picture 2); it is also referred to as "erythropoietic hemochromatosis." Its magnitude is most closely related to the duration of the disease and the degree of erythroid hyperplasia/ineffective erythropoiesis in the bone marrow [117-119]. In XLSA, the iron burden does not always correlate with the severity of anemia, and cirrhosis may be encountered in asymptomatic individuals with mild or previously unrecognized anemia, or anemia that has responded to pyridoxine, due to the increased deposition of iron within the liver (picture 3) [117,120-122]. Hepatocellular carcinoma developed in two reported cases [76]. Cardiomyopathy (picture 4) and endocrine deficits may be seen.

The body iron burden is further increased by transfusions given for severe anemia or by inappropriate administration of iron based on an incorrect diagnosis of iron deficiency. Co-inheritance of a common hemochromatosis gene (HFE) variant such as C282Y or H63D, which would increase intestinal iron absorption, has been rarely observed [123-125]. Concomitant HFE variants were excluded in several patient series with congenital or acquired clonal sideroblastic anemia [119].

The extent to which iron overload accentuates the anemia in patients with sideroblastic anemia is difficult to assess. Instances in which anemia was improved by iron depletion have been reported [126,127]. These observations suggest that reducing iron overload may improve erythroblast mitochondrial function, erythropoiesis, and hypersplenism [1]. Pyridoxine responsiveness may also be enhanced upon iron depletion in some cases of XLSA [124].

DISORDERS OF HEME SYNTHESIS WITHOUT RING SIDEROBLASTS — 

Many disorders of heme synthesis are not associated with sideroblastic anemia.

Porphyrias — Porphyrias are inherited disorders of heme biosynthesis, each caused by genetic defects in one of the eight enzymes of the heme biosynthetic pathway. Most porphyrias are not associated with compromised erythropoiesis, anemia, or ring sideroblasts, because the affected enzymes have tissue-specific expression and/or regulation predominantly in nonerythroid cells.

Exceptions include the following two porphyrias:

●EPP – As noted above, erythropoietic protoporphyria (EPP), which is caused by mutations affecting the enzyme ferrochelatase (FECH), can be associated with ring sideroblasts. (See 'Autosomal recessive congenital sideroblastic anemia' above and "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'EPP due to FECH variant'.)

●CEP – Congenital erythropoietic porphyria (CEP) has a hemolytic anemia that is caused by marked accumulation of the heme synthesis intermediate isomer uroporphyrinogen I, but CEP is not associated with ring sideroblasts. (See "Porphyrias: Overview of classification and evaluation" and "Congenital erythropoietic porphyria".)

Lead poisoning — Lead poisoning is frequently listed as a cause of sideroblastic anemia, and the anemia of lead poisoning results in part from inhibition of heme synthesis. However, authentic ring sideroblasts have not been convincingly documented in lead poisoning. Examination of iron-stained bone marrow aspirate smears from 12 patients with established lead toxicity and anemia of varying severity did not reveal ring sideroblasts in any of the patients [128].

Lead inhibits most of the enzymes in the heme biosynthetic pathway to varying degrees, ALA dehydratase (ALAD) being the most sensitive [69]. Lead also limits iron delivery to ferrochelatase (FECH) in erythroid cells. As a result, zinc is inserted into protoporphyrin as a surrogate metal, producing zinc protoporphyrin, which also occurs in iron deficiency. The reduced availability of iron is likely responsible for the absence of ring sideroblasts in individuals with lead poisoning.

Lead poisoning can cause hemolysis as well as other manifestations in multiple organ systems. (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Lead exposure, toxicity, and poisoning in adults: Clinical manifestations and diagnosis".)

SUMMARY

●Definition – Sideroblastic anemias are anemias in which ring sideroblasts are seen on Prussian blue-stained bone marrow aspirate smears. Ring sideroblasts represent red blood cell (RBC) precursors in which pathologic iron deposits have accumulated in mitochondria in a perinuclear ring distribution (picture 1). (See 'Pathophysiology' above.)

●Congenital causes – Congenital sideroblastic anemias are caused by a germline pathogenic variant in a nuclear or mitochondrial gene(s). They can be further classified into syndromic and nonsyndromic forms (table 1). Inheritance can be X-linked, autosomal recessive, or mitochondrial. The RBCs can be microcytic or normal-to-macrocytic (table 2). Specific genetic defects and their associated features are described above. (See 'Congenital sideroblastic anemias' above.)

●MDS and MPNs – Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders typically acquired in adulthood. Some MDS/MPN variants are characterized by ring sideroblasts, usually in the setting of an acquired mutation in SF3B1. (See 'Clonal (MDS/MPN subtypes)' above.)

●Alcohol, medications, copper deficiency – Reversible acquired sideroblastic anemia can be caused by exposure to alcohol, certain medications (eg, isoniazid [INH], chloramphenicol, and linezolid), and hypothermia, and by copper deficiency. (See 'Reversible' above.)

●Effects on heme synthesis – The pathophysiologic mechanisms of ring sideroblast formation are centered in erythroblast mitochondria and involve defective heme synthesis, deficient formation of iron-sulfur clusters for proteins regulating heme synthesis, or abnormalities in production of mitochondrial proteins in RBC precursors (figure 1); these block the intracellular utilization of iron, resulting in its trapping and accumulation in mitochondria. Vitamin B6 (pyridoxine) is a cofactor for the initial heme synthetic enzyme 5-aminolevulinic acid synthase (ALAS2). Copper plays a role in mitochondrial redox reactions via cytochrome c oxidase. (See 'Disrupted mitochondrial pathways in erythroid precursors' above.)

●Effects on RBC production – Several common sideroblastic anemias are associated with ineffective erythropoiesis, a process of disrupted erythroblast maturation with destruction in the bone marrow. Ineffective erythropoiesis in turn leads to suppressed hepcidin production, increased intestinal iron absorption, and systemic iron overload, which is further exacerbated by transfusions. (See 'Ineffective erythropoiesis and iron overload' above and "Regulation of iron balance".)

●Heme synthesis abnormalities that do not cause sideroblastic anemia – Pathogenic variants in all of the genes encoding heme synthetic enzymes cause porphyria without sideroblastic anemia with the exception of erythropoietic protoporphyria (EPP; associated with pathogenic variants in ferrochelatase [FECH]). In our experience, lead poisoning is not a cause of sideroblastic anemia. (See 'Disorders of heme synthesis without ring sideroblasts' above.)

●Evaluation and treatment – An approach to the evaluation, diagnosis, and treatment of sideroblastic anemias is presented separately. (See "Sideroblastic anemias: Diagnosis and management".)

ACKNOWLEDGMENT — 

UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.