Causes and pathophysiology of the sideroblastic anemias

INTRODUCTION — Sideroblastic anemias are anemias in which ring sideroblasts are present on the bone marrow aspirate smear stained for iron with Prussian blue. Ring sideroblasts are found in diverse circumstances, which underscores a broad spectrum of causes of sideroblastic anemia, both inherited and acquired (table 1). Understanding the causative mechanisms is useful for predicting the disease course and guiding therapy, which differ for the various sideroblastic anemia forms.

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

CAUSES OF SIDEROBLASTIC ANEMIAS — The conventional classification of the sideroblastic anemias is structured on whether the cause is congenital (inherited) or acquired, followed by listing genetic defects 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 (table 2).

Congenital sideroblastic anemias — Congenital sideroblastic anemias are caused by a germline pathogenic variant affecting a nuclear or mitochondrial gene. For a number of forms, underlying defects have been established at the molecular level, as illustrated in the diagram (figure 1). However, approximately one-third of cases do not have an identifiable genetic defect as of yet [3-5]. The causative defects for these patients are actively being sought in research laboratories.

The congenital sideroblastic anemias 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 appear as nonsyndromic, with isolated anemia and ring sideroblasts in the bone marrow. The syndromic forms, which affect other organ systems, are very uncommon.

Nonsyndromic forms — Most congenital sideroblastic anemias are nonsyndromic. They can be X-linked, referred to as X-linked sideroblastic anemia (XLSA) or autosomal recessive, referred to as autosomal recessive congenital sideroblastic anemia (ARCSA).

X-linked sideroblastic anemia (ALAS2 mutation) — 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) was established in several kindreds [1]. The ALAS2 enzyme catalyzes the first and rate-limiting step in heme synthesis (condensation of glycine and succinyl-CoA to ALA) (figure 2) and is essential for erythroid cell development [6,7]. (See 'Heme synthesis' below.)

Over 100 distinct pathogenic variants in ALAS2 have been identified among more than 130 unrelated kindreds or probands. These variants are most often missense mutations that affect the catalytic domain of ALAS2 and reduce enzymatic function in many but not all cases [1,8]. Uncommon are nonsense mutations, nucleotide deletions, synonymous coding variant altering ALAS2 splicing, mutations in a GATA1 transcription factor binding site in intron 1, and regulatory mutations in the ALAS2 promoter region; null mutations are seen only in heterozygous females [1,8-11].

ALAS2 is located on the X chromosome [12,13]. Although XLSA is most commonly seen in males, nearly one-third of affected individuals are females who manifest the disorder because they develop highly skewed X inactivation in hematopoietic cells, favoring expression of the mutant allele [14-17]. (See "Sideroblastic anemias: Diagnosis and management", section on 'Diagnostic approach'.)

Autosomal recessive congenital sideroblastic anemia (pathogenic variant in SLC25A38, GLRX5, HSPA9, HSCB, or FECH) — Pathogenic variants in several genes involved in heme synthesis cause autosomal recessive congenital sideroblastic anemia (ARCSA) (figure 1). Among the ARCSAs, the one associated with SLC25A38 mutations is the most common, second only to XLSA in occurrence [18].

●SLC25A38 – SLC25A38 encodes an erythroid-specific mitochondrial amino acid carrier that transports glycine into mitochondria for the first step in heme synthesis [19]. Multiple biallelic mutations in the SLC25A38 gene associated with congenital sideroblastic anemia have been identified in at least 93 families or probands [18].

●HSPA9 and HSCB – HSPA9 encodes the mitochondrial HSP70 homologue HSPA9, which is also involved in Fe-S cluster biogenesis. Heterogeneous biallelic mutations have been discovered in 12 families or isolated cases [20,21]. In one patient, biallelic mutations in HSCB, which encodes a co-chaperone of HSPA9, are reported [22].

●GLRX5 – GLRX5 encodes a small protein required for the synthesis of iron-sulfur (Fe-S) clusters, prosthetic groups that are essential components of various mitochondrial and cytosolic proteins, including iron regulatory protein 1 (IRP1) and ferrochelatase (FECH) [23]. In a zebrafish mutant (shiraz) deficient in GLRX5, IRP1 cannot acquire the Fe-S cluster and thus inhibits ALAS2 translation, causing severe hypochromic anemia [24]. Homozygous and heterozygous biallelic pathogenic variants in GLRX5 have been described in three patients [25-27].

●FECH – FECH encodes ferrochelatase, the final enzyme in the heme synthetic pathway, which inserts an iron atom into protoporphyrin IX (figure 2). Mutations in FECH cause erythropoietic protoporphyria (EPP), in which patients develop acute, nonblistering cutaneous photosensitivity due to accumulation of excess free protoporphyrin. Most if not all individuals with EPP have mild microcytic anemia. Ring sideroblasts have been documented in only 10 patients but not in others [28-30]. 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 forms — Syndromic congenital sideroblastic anemias have other, nonhematologic manifestations such as neuromuscular and metabolic abnormalities in addition to the ring sideroblast feature (table 1 and table 2).

X-linked sideroblastic anemia with ataxia (ABCB7 mutation) — X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare phenotype of congenital sideroblastic anemia, characterized by relatively mild anemia and nonprogressive spinocerebellar ataxia [31]. The molecular defect resides in the ABCB7 gene, which is located on the X chromosome. It encodes an essential transporter in the inner mitochondrial membrane [32]. This transporter is involved in the transfer of Fe-S clusters into the cytoplasm for assembly of cytoplasmic Fe-S cluster-containing proteins [33]. Several mutations have been described and 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 (pathogenic variants in IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2) — Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) was first defined as an autosomal recessive oxidative phosphorylation disorder in 2004, characterized by progressive exercise intolerance during childhood, onset of sideroblastic anemia usually around adolescence, basal lactic acidemia, and mitochondrial myopathy due to mutation of PUS1 (pseudouridine synthase 1) [37,38]. The IARS2, LARS2, PUS1, SARS2, and YARS2 variants are also autosomal recessive, while those associated with a recurrent mutation of NDUFB11 or MT-ATP6 are X-linked and maternally inherited, respectively. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Predominantly multisystem disease with myopathy'.)

Pathogenic variants in the IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, and YARS2 genes are found in individuals with, in part, similar syndromic findings, ranging from mild (not detected until adulthood) to lethal in severity [38-47]; among cases with YARS2 defects, isolated sideroblastic anemia without syndromic features has been noted [44]. Five nuclear genes (IARS2, LARS2, PUS1, SARS2 and YARS2) involve mitochondrial protein translation, while NDUFB11 encodes a component of the respiratory chain complex I [41,48]. Mitochondrial MT-ATP6 encodes ATPase 6, a component of complex V (ATPase) [40,45]. (See 'Mitochondrial protein synthesis' below.)

Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (TRNT1 mutation) — Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (SIFD; also called ARCSA with immunodeficiency) is a congenital syndromic immunodeficiency associated with severe microcytic sideroblastic anemia, 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, including milder phenotypes such as manifesting only isolated anemia or immunodeficiency, or isolated nonsyndromic retinitis pigmentosa with microcytic red blood cells [51,52]. Early death was commonly attributed 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 affecting TRNT1 [50]; this nuclear 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 engage in the polypeptide assembly on ribosomes. Transmission is autosomal recessive, and parental consanguinity was present in several instances [49-52]. (See 'Mitochondrial protein synthesis' below.)

Pearson syndrome (large deletion of mitochondrial DNA) — Pearson syndrome (Pearson marrow pancreas syndrome) 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 patients with onset later than previously reported [53]. 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 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 (SLC19A2 mutation) — Thiamine-responsive megaloblastic anemia (TRMA, also called Rogers syndrome) is a congenital syndrome characterized by megaloblastic anemia, diabetes mellitus, and sensorineural deafness manifesting between infancy and adolescence [56]. Hematologic findings also include the ring sideroblast abnormality and variable degrees of neutropenia and thrombocytopenia. (See "Macrocytosis/Macrocytic anemia", section on 'Megaloblastic anemia'.)

TRMA is caused by mutations in the SLC19A2 gene, which encodes a high-affinity thiamine transporter protein, with various mutations identified in many families [56-59]. Transmission is autosomal recessive.

Acquired sideroblastic anemias — Acquired sideroblastic anemias are subdivided into the clonal forms (myelodysplastic syndromes with ring sideroblasts [MDS-RS]) and the forms that are reversible, due to an exposure or deficiency that affects aspects of erythroblast iron handling (table 1). In the reversible forms such as exposure to ethanol and 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). Exceptions are exposure to isoniazid and alcohol, which cause microcytic anemia. 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, granulocytes, and/or platelets. 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)

A very close association between the ring sideroblast feature in these MDS/MPN variants and specific somatic mutations in genes implicated in mRNA splicing suggested a causal relationship.

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 (<10 percent) [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 acquired sideroblastic anemias other than the MDS/MPN forms is the reversibility following correction of the underlying abnormality (assuming it can be identified).

Alcohol — The ring sideroblast abnormality is one of many components 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 antibacterial antibiotics chloramphenicol and linezolid.

●Isoniazid (INH) – While INH has been extensively used to treat tuberculosis for over six 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 regular co-administration of pyridoxine (vitamin B6) to prevent the common 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. High-quality evidence that the related drugs pyrazinamide and cycloserine cause sideroblastic anemia is lacking.

INH interference with pyridoxine metabolism and thus with the function of the ALAS2 enzyme is considered to be the basis for sideroblastic anemia occurring in some individuals. 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 remote 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.)

●Cytotoxic chemotherapy – Anecdotal cases over 40 years ago suggested that when sideroblastic anemia followed chemotherapy for hematologic malignancies, subsequent leukemic evolution was the rule [1]. The role of the ring sideroblast abnormality in therapy-related myelodysplastic syndrome (t-MDS) was subsequently explored. In a study involving 843 patients who were initially diagnosed as having secondary MDS months to years following cytotoxic chemotherapy for various malignancies, 19 had a normal karyotype, <5 percent blasts in the bone marrow, and abundant ring sideroblasts [73]. Six of these 19 (32 percent) had normalization of the complete blood count (CBC) and resolution of signs of dyserythropoiesis and the ring sideroblast abnormality on subsequent bone marrow examinations, indicating that they had a reversible sideroblastic anemia rather than MDS, although a specific cause could not be identified. In a later study comparing 38 patients having t-MDS and ring sideroblasts (t-MDS-RS) with 174 patients having de novo MDS and ring sideroblasts (de novo MDS-RS), the t-MDS-RS cohort had the following features [74]:

•A higher prognostic risk by cytogenetic score and revised international prognostic scoring system for MDS (IPSS-R), often carrying pathogenic variants in TP53.

•Less commonly, pathogenic variants in SF3B1 and spliceosome-related genes (approximately 33 percent versus approximately 75 percent), suggesting other mechanisms for the ring sideroblast feature.

•A worse outcome, similar to that of t-MDS without ring sideroblasts.

Attention to the "short-term gain but long-term pain" from cytotoxic chemotherapy as reflected in the risk of t-MDS in general is gaining momentum [75]. Prevention strategies have been proposed such as revision of chemotherapy agent use (eg, alkylating agents) and clinical sequencing at diagnosis to aid identification of patients at risk for t-MDS.

Hypothermia — A sideroblastic abnormality has been described in three patients with episodic hypothermia [76]. This cause was thought to involve the known sensitivity of several mitochondrial functions to reduced temperature (eg, translocation of proteins into mitochondria, heme synthesis, and iron incorporation into hemoglobin) [1].

Copper deficiency — Although uncommon, copper deficiency is a cause of sideroblastic anemia, along with neutropenia, and is commonly accompanied by various 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. (See "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency'.)

A rare cause of copper deficiency was reported in an infant with a familial nephrotic syndrome associated with a mutation in the NPHS2 gene, which encodes a renal glomerular protein implicated in nephrotic syndrome. The presumed mechanism was attributed to urinary losses of ceruloplasmin and copper.

Transient sideroblastic anemia during pregnancy — Several reports have described sideroblastic anemia manifesting during pregnancy [77,78]. The sideroblastic anemia recurred in successive pregnancies or was detected postpartum. Molecular analysis for a hereditary cause was not performed in these cases.

In one instance, low vitamin B6 level was documented and supplements increased the Hb level [77]. A carrier state of a genetic variant that becomes clinically expressed is a possibility in these individuals and should be excluded. For example, an otherwise clinically occult pathogenic variant in ALAS2 (XLSA) may become expressed if there is skewed X inactivation, and the anemia would respond to pyridoxine supplementation as vitamin B6 stores can be reduced during pregnancy. Explanation of this unusual occurrence requires at least molecular studies as well as comprehensive data that are lacking on nutritional sufficiency of vitamin B6 during pregnancy generally. (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Vitamin B6'.)

PATHOPHYSIOLOGY — The causes of sideroblastic anemia most often lead to defective maturation of developing erythroid cells (erythroblasts) from disturbances in the production of heme for hemoglobin. In this setting, the bone marrow characteristically responds to the anemic hypoxia by increasing erythropoiesis, which is ineffective due to the maturation defects. Moreover, the ineffective erythropoiesis itself elicits an associated systemic iron overload state that influences clinical features and prognosis. (See 'Iron overload' below and "Sideroblastic anemias: Diagnosis and management", section on 'Laboratory and bone marrow findings'.)

Disrupted mitochondrial pathways in erythroid precursors — Mitochondria of 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. Rather, each known cause that leads to a sideroblastic anemia disrupts one or more of four mitochondrial metabolic pathways [2,79]:

●Heme synthesis

●Iron sulfur-cluster production

●Mitochondrial protein synthesis

●Oxidative phosphorylation

In sideroblastic anemias, iron is delivered to erythroblast mitochondria normally [80,81]. However, the disrupted mitochondrial pathway(s) blocks the iron utilization that occurs exclusively in mitochondria, and a feedback mechanism to reduce iron import into mitochondria is not known. Consequently, iron accumulates in the mitochondrial matrix as mitochondrial ferritin, forming the ring sideroblast [82,83]. This diagnostic feature of any sideroblastic anemia is detected on the iron-stained bone marrow aspirate smear, revealing erythroblasts containing numerous coarse blue "granules" that characteristically appear strung out like a necklace or a ring around the cell nuclei (picture 1). Ultrastructurally, the granules represent pathological, iron-laden mitochondria (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 subsequent enzymes in the heme synthesis pathway [1]. The transcriptional expression of these enzymes is mediated by erythroid-specific factors, similar to 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 [84].

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 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(s) within the ALAS2 enzyme, thereby determining its impact on the enzyme's function [8,85,86]. Despite the X-linked inheritance pattern, and in contrast with most if not all X-linked disorders, about one-third of affected individuals are female [1]. This high rate of expression in females is due to highly skewed X chromosome inactivation, which occurs in hematopoietic tissue with advancing age, favoring expression of mostly the abnormal allele. (See "Genetics: Glossary of terms", section on 'X-inactivation'.)

Their pathogenic variants in ALAS2 tend to be more damaging to the enzyme, which is reenforced by the virtual absence of male offspring of affected females [1,15]. In exceptional cases, there may be "constitutional" skewing of X chromosome inactivation that causes the disease to manifest in females earlier in life [14]. The mechanism of XLSA in a first reported female fetus is unclear [87]. (See 'X-linked sideroblastic anemia (ALAS2 mutation)' above.)

Pyridoxine (vitamin B6) is converted in the liver to the active co-enzyme pyridoxal-5’-phosphate, an obligate cofactor for ALAS. In up to two-thirds of patients with XLSA, 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 [85].

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 [88].

•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 [89].

●Mitochondrial transporter SLC25A28 variants – The erythroid-specific carrier protein SLC25A38 imports glycine across the inner mitochondrial membrane; large amounts of glycine are required as a substrate for ALAS to generate ALA [19,90]. Biallelic mutations in SLC25A38 are associated with severe anemia from infancy [18]. Most of the mutations are complete loss-of-function mutations or severe mutations that markedly compromise the function of the protein and in turn severely impair heme synthesis. Interestingly, in one case, the condition occurred due to uniparental (paternal) isodisomy [91]. (See 'Autosomal recessive congenital sideroblastic anemia (pathogenic variant in SLC25A38, GLRX5, HSPA9, HSCB, or FECH)' above.)

●Ferrochelatase deficiency – Ferrochelatase (FECH) catalyzes the final step in heme syntheses. Marked deficiency of FECH is due to numerous identified mutations affecting the enzyme, which cause the autosomal recessively (or "pseudo-dominantly") inherited erythropoietic protoporphyria (EPP). EPP is manifested in erythroid cells by marked accumulation of 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 [92]. (See 'Autosomal recessive congenital sideroblastic anemia (pathogenic variant in SLC25A38, GLRX5, HSPA9, HSCB, or FECH)' above.)

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

●Isoniazid (INH) administration – INH is an antituberculosis agent that interferes with the function of ALAS2 and in turn impairs 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 [93].

●Excess alcohol use – The ring sideroblast feature 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 [69,94]. Toxic effects on mitochondrial protein synthesis are involved, 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 proteins regulating cellular iron uptake, heme synthesis, and iron storage, including iron regulatory protein 1 (IRP1) as well as FECH itself [95]. Fe-S clusters are synthesized exclusively in mitochondria via a multistep process and are then incorporated into mitochondrial as well as cytoplasmic recipient proteins [95].

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

●HSPA9 and HSCB – HSPA9 and its co-chaperone HSCB are involved in mitochondrial Fe-S cluster biogenesis and transfer of nascent Fe-S clusters to glutaredoxin 5 for their transport to target proteins [2]. Impaired HSPA9 and HSCB proteins due to heterogeneous biallelic pathogenic variants would lead secondarily to repressed ALAS2 translation, similar to that seen with GLRX5 and ABCB7, discussed immediately below. In some cases, a single severe HSPA9 loss-of-function allele is associated with a common single nucleotide polymorphism in the other HSPA9 allele that is under-expressed, resulting in a pseudodominant inheritance pattern [20]. (See 'Autosomal recessive congenital sideroblastic anemia (pathogenic variant in SLC25A38, GLRX5, HSPA9, HSCB, or FECH)' above.)

●Glutaredoxin 5 (GLRX5) deficiency – GLRX5 distributes Fe-S clusters to Fe-S requiring proteins. Pathogenic variants in GLRX5 result in lack of Fe-S clusters in IRP1, thereby activating IRP1 to its RNA binding form and leading to repression of ALAS2 translation and impaired heme synthesis [23]. Because FECH requires an Fe-S cluster for its function, FECH levels are also decreased. (See 'Autosomal recessive congenital sideroblastic anemia (pathogenic variant in SLC25A38, GLRX5, HSPA9, HSCB, or FECH)' 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 [33,95]. 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 [96]. (See 'X-linked sideroblastic anemia with ataxia (ABCB7 mutation)' above.)

The pathogenesis of the associated neurologic manifestations is unclear. As in Friedreich ataxia, 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 manifestations are associated with diverse genetic defects involving mitochondrial proteins that are unrelated to heme synthesis and Fe-S protein production per se. 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 transmitted; these proteins represent components of respiratory chain complexes. For their translation, the mitochondrial genome encodes 12 mitochondrial transfer RNAs (tRNAs) and 2 mitochondrial ribosomal RNAs [97]. This dual genetic control of the mitochondrial proteins and their function adds to the difficulty in the interpretation of pathological findings and phenotypic features of these syndromes.

How these mitochondrial protein synthesis defects 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 normal or macrocytic in most cases. The recurrent involvement of components of the respiratory chain in these syndromes may in part affect iron utilization in the erythroid cell, but the mechanism(s) is not understood [98]. The understanding of the genetic mitochondrial cytopathies is further obscured by the lack of an explanation as to why defects 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 forms' above.)

●Heteroplasmy of large deletions, rearrangements, or duplications of mitochondrial DNA – These usually sporadic aberrations lead to the loss of multiple proteins encoded by the mitochondrial genome in Pearson syndrome (see 'Pearson syndrome (large deletion of mitochondrial DNA)' above). 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.

●Mitochondrial tyrosyl-tRNA synthetase (YARS2) – The synthetase YARS2 attaches tyrosine to its cognate tRNA. Mutations in YARS2 reduce levels of the enzyme and affect production of respiratory complex proteins encoded by the mitochondrial genome [42]. 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 (pathogenic variants in IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2)' above.)

●Mitochondrial leucyl-tRNA synthetase (LARS2) – The synthetase LARS2 attaches leucine to its cognate tRNA. Mutations 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 (pathogenic variants in IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2)' above.)

●Mitochondrial isoleucyl-tRNA synthetase (IARS2) – The synthetase IARS2 attaches isoleucine to its cognate 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 [46]. Respiratory chain deficiency affecting erythropoiesis is implicated. (See 'Myopathy, lactic acidosis, and sideroblastic anemia (pathogenic variants in IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2)' above.)

●Mitochondrial seryl-tRNA synthetase (SARS2) – The synthetase SARS2 attaches serine to its cognate 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 [47]. 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 (pathogenic variants in IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2)' above.)

●Pseudouridine synthase (PUS1) – Mutated PUS1 results in defective pseudo-uridylation of uridine, destabilizing tRNA structures and likely causing faulty translation of mitochondrial genes of respiratory complexes I and IV [99]. (See 'Myopathy, lactic acidosis, and sideroblastic anemia (pathogenic variants in IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2)' above.)

●tRNA nucleotidyl transferase (TRNT1) – The TRNT1 enzyme is essential for processing all cytosolic and mitochondrial precursor tRNAs by adding the trinucleotide CCA to their 3" end for protein synthesis globally. As noted above (see 'Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (TRNT1 mutation)' above), pathogenic variants in TRNT1 lead to metabolic dysfunctions in multiple body systems, but their pathogenesis is not defined. At the cellular level, formation of respiratory chain complexes was impaired in patient-derived fibroblasts [100]. 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 [51,101].

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 [102]. Impaired heme synthesis, evident in reduced FECH activity, appears to be a secondary effect [94]. (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 mutation 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 [41,48]. (See 'Myopathy, lactic acidosis, and sideroblastic anemia (pathogenic variants in IARS2, LARS2, MT-ATP6, NDUFB11, PUS1, SARS2, or YARS2)' above.)

•ATPase 6 – A recurrent heteroplasmic mutation 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 [40,45]. Varying degrees of heteroplasmy correlate with variable clinical manifestations.

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

●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, disorders 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 [103,104]. However, ABCB7 has a reduced transcript and emerged as a leading candidate gene involved in causing the ring sideroblast abnormality [103,105,106]. Further, the aberrant splicing caused by mutant SF3B1 produces a premature termination codon in the ABCB7 mRNA, resulting in nonsense-mediated mRNA decay [107].

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 [108,109]. Reduced protein expression of mis-spliced ABCB7 and TMEM14C (the 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 [108].

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 (ABCB7 mutation)' above and 'Autosomal recessive congenital sideroblastic anemia (pathogenic variant in SLC25A38, GLRX5, HSPA9, HSCB, or FECH)' 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 (SLC19A2 mutation)' above.)

The pathophysiology of this syndrome is unclear, and multiple pathways appear to be involved. The megaloblastic anemia in TRMA was thought to result from defective nucleic acid synthesis attributed to cellular thiamine deficiency [110]. The associated ring sideroblasts observed in TRMA was hypothesized to relate to the role of thiamine in the production of succinyl-coenzyme A, a substrate of ALAS [111]. 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, it is suggested to provide a potential 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 [112]. The anemia is 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 [113]. 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 [114].

Ineffective erythropoiesis and iron overload — Ineffective erythropoiesis is a major 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 thalassemias [115-117]. 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 response 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) through its secretion by the expanded but ineffective erythron in the bone marrow [118]. 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 [119]. 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 [119].

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 in the bone marrow [120-122]. In XLSA the iron burden has not always correlated 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) [120,123-125]. Hepatocellular carcinoma developed in two reported cases [79]. 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 [126-128]. Concomitant HFE variants were excluded in several patient series with congenital or acquired clonal sideroblastic anemia [122].

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 [129,130]. 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 [127].

DISORDERS OF HEME SYNTHESIS WITHOUT RING SIDEROBLASTS — Many disorders of heme synthesis are not associated with sideroblastic anemia, as discussed in the following.

Porphyrias — Porphyrias are inherited disorders of heme biosynthesis, each caused by genetic defects in one of the eight enzymes of the heme biosynthesis pathway. Most porphyrias are not associated with compromised erythropoiesis, anemia, or the ring sideroblast abnormality, 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 (pathogenic variant in SLC25A38, GLRX5, HSPA9, HSCB, or FECH)' 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: An overview" 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. On our review of the iron-stained bone marrow aspirate smears from 12 patients with established lead toxicity and anemia of varying severity, we were unable to detect ring sideroblasts in any of their bone marrow smears [131].

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, similar to the process that 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".)

SUMMARY

●Definition – Sideroblastic anemias are anemias in which ring sideroblasts are seen on a Prussian blue-stained bone marrow aspirate smear. 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 (MPN) 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, linezolid, and cytotoxic chemotherapy), 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 (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.