anemias sideroblasticas jbc2002

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2002 Blackwell Science Ltd.Volume 116(4-II) March 2002 pp 733-743

Sideroblastic anaemias[Review]

Alcindor, Thierry; Bridges, Kenneth R.

Division of Haematology, Brigham and Women's Hospital andHarvard Medical School, Boston, MA, USA

Correspondence: Kenneth R. Bridges, Brigham and Women'sHospital, 75 Francis Street, Midcampus 3, Boston, MA 02115,USA. E-mail: [email protected]

Outline

Hereditary sideroblastic anaemias X-linked sideroblastic anaemia Other hereditary forms of sideroblastic anaemia Mitochondrial cytopathies

Acquired sideroblastic anaemias Myelodysplastic syndromes Drug- and toxin-induced sideroblastic anaemias Nutritional factors

Clinical manifestations and diagnosis Treatment

Conclusion References

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Figure 1 Table I. Categories ...

The sideroblastic anaemias are a heterogeneous group of disorders whose two distinctive

features are ring sideroblasts in the bone marrow (abnormal erythroblasts with excessiveiron accumulation in the mitochondria) and impaired haem biosynthesis ( Bottomley, 1982;May & Fitzsimons, 1994 ). The aetiology, epidemiology, pathophysiology and treatment of these conditions differ vastly. The mitochondrion is the nexus of sideroblastic anaemia,however. Disturbed mitochondrial metabolism characterizes all sideroblastic anaemias inwhich a cause has been determined.

Figure 1 is a simplified schema of haem biosynthesis. The process begins in themitochondrion with the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA) with pyridoxal phosphate as a cofactor ( Bottomley & Muller-Eberhard,1988 ). ALA then moves to the cytoplasm where several additional enzymatictransformations produce coproporphyrinogen III. This molecule enters the mitochondrionwhere additional modifications, including the insertion of iron into the protoporphyrin IXring by ferrochelatase, produce haem.

Figure 1. Simplified schema of haem biosynthesis. Haem biosynthesis begins in the mitochondrion with thecondensation of succinyl-CoA and glycine to form 5-aminolevulinic acid (delta-aminolevulinic acid). Biosynthesismoves to the cytosol where multiple enzymatic steps produce coproporphyrinogen III. This molecule enters themitochondrion for the final steps of haem biosynthesis.

Numerous studies of various subtypes of sideroblastic anaemias demonstrate impairedhaem production ( Vogler & Mingioli, 1968; Konopka & Hoffbrand, 1979; Pasanen et al, 1985 ). Mostcommonly, the sideroblastic anaemias are classified as hereditary or acquired conditions(Table I ). The hereditary forms are primarily X-linked, although some families displayautosomal dominant or autosomal recessive modes of transmission ( Amos et al, 1988 ).Isolated cases of congenital sideroblastic anaemia often defy classification as they lack the well-documented pedigrees needed to firmly establish modes of transmission ( Dolan &Reid, 1991 ).

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Table I. Categories of sideroblastic anaemia.

The acquired sideroblastic anaemias are far more common than the hereditary varieties.Drugs and toxins lead this category, propelled largely by the high frequency of alcohol

abuse in many societies ( Pierce et al, 1976; Larkin & Watson-Williams, 1984 ). The next largestsubgroup, refractory anaemia with ring sideroblasts, is itself a subset of themyelodysplastic syndromes (MDS) ( Hast, 1986 ). Hypothermia is a rare antecedent of sideroblastic anaemia ( O'Brien et al, 1982 ).

The exact mechanism by which disturbed haem metabolism produces sideroblasticanaemias remains elusive. Haem is an essential component of many mitochondrialenzymes (e.g. cytochromes b, c 1, c, a, a 3) as well as cytosolic enzymes such as catalase(Verkhovsky et al, 1996; Barros et al, 2001; Matsuno-Yagi & Hatefi, 2001 ). The molecule is also anintegral component of haemoglobin in which it has both structural and functional roles.Haem modulates translation of globin mRNA, stabilizes the globin protein chains andmediates reversible oxygen binding.

5-aminolevulinic acid synthase (ALAS) is both the first and rate-limiting enzyme in haem biosynthesis ( Bottomley & Muller-Eberhard, 1988 ). Haem modulates its activity throughfeedback inhibition. The gene that encodes ALAS-1 (also called ALAS-n) resides onchromosome 3 (3p21) ( Bishop et al, 1990 ). This ubiquitous enzyme is particularly abundantin the liver. ALAS-1 provides the basal haem production needed by all cells andmaintains a relatively stable level.

The enzyme directly relevant to sideroblastic anaemia is ALAS-2 or ALAS-e (erythroid).The gene encoding this enzyme exists on the X chromosome (Xp11.21), with expressionrestricted to the erythroid lineage ( Cox et al, 1990; Cotter et al, 1992a ). ALAS-2 activity lacksknown feedback regulation by haem. The enzyme is, however, a member of a smallfamily of genes whose expression is modulated by iron ( Cox et al, 1991; Bhasker et al, 1993;Melefors et al, 1993 ).

The best-characterized genes of this family are those encoding ferritin and the transferrinreceptor ( Klausner & Harford, 1989 ). Ferritin mRNA contains a conserved stem-loop sequencein the 5'-untranslated region called the iron response element (IRE). A homologoussequence exists in the 5'-untranslated region of the ALAS-2 message ( Dandekar et al, 1991 ).In contrast, transferrin receptor mRNA has five IRE elements all in the 3'-untranslated

region.

Two cytoplasmic proteins called the iron regulatory proteins 1 and 2 (IRP1 and IRP2) bind to the IRE regions of the messenger RNA. In the absence of iron, IRP1 binds to theIRE elements in the 5'-untranslated regions of the messages encoding ferritin and ALAS-2 (Melefors et al, 1993 ). The IRE/IRP complex blocks message translation, dampening the

biosynthesis of ferritin and ALAS-2. This response makes teleological sense. In theabsence of iron, the cell does not need the iron storage protein, ferritin. Similarly, in theabsence of iron, erythroid precursors need not produce protoporphyrin IX as this moleculecannot be converted to haem.

The signal feature of sideroblastic anaemia is mitochondrial iron deposition ( Koc & Harris,1998 ). Erythroid precursors stained for iron with Perl's Prussian blue often show two or
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three bluish green inclusions called siderosomes. The cells that contain these irongranules are called sideroblasts. In sideroblastic anaemia, the iron-containing particles arelarger and more numerous. Many erythroblasts contain six or more blue-green particlesthat ring the nucleus creating the pathognomonic ring sideroblast. Ring sideroblastscomprise between 15% and 50% of the erythroblasts in most patients while some display

only ring sideroblasts on bone marrow examination.

Electron microscopy shows crystalline iron deposits between cristae in the matrix of themitochondrion ( Grasso & Hines, 1969 ). The basis of this phenomenon is unknown. Simplecellular iron overload is not the answer. Massive cellular iron overload occurs in bothhereditary and transfusional haemochromatosis. Neither disorder manifests iron ladenmitochondria. Sideroblasts show normal iron uptake, but subsequent poor incorporationinto haem ( May et al, 1982 ). Mishandling of iron by mitochondria could be the basis of theiron deposits. Production of protoporphyrin in quantities insufficient to acceptmitochondrial iron would theoretically create a scenario conducive to mitochondrial ironaccumulation. Our limited understanding of mitochondrial iron metabolism has, however,

precluded testable hypotheses.

Mitochondrial iron deposits could be more than morphological curiosities. Iron catalysesthe formation of reactive oxygen species through Fenton chemistry ( Liochev & Fridovich,1994 ). Molecules such as the hydroxyl radical ( OH) arise in settings in which oxidationreactions occur in proximity to iron ( Gutteridge et al, 1981 ). The oxidative metabolicmachinery of the mitochondrion creates an ideal environment for the generation of reactive oxygen species. The primary damage in sideroblastic anaemia that produces iron-laden mitochondria could create a feedback loop with escalating mitochondrial injury.The hydroxyl radical, for instance, promotes lipid and protein peroxidation as well ascross-links in DNA strands ( Park & Floyd, 1992; Thomas et al, 1993 ). The latter phenomenoncould be particularly injurious given the dearth of DNA repair enzymes in mitochondria(Boore, 1999 ).

Reports exist of patients whose sideroblastic anaemia improved when their iron overloadwas reduced through phlebotomy ( French et al, 1976; Cotter et al, 1999 ). Phlebotomy could havereduced iron-mediated injury to erythroblasts in these patients. Patients with sideroblasticanaemia show enhanced apoptosis of bone marrow cells relative to normal ( Fontenay-Roupieet al, 1999; Matthes et al, 2000 ). When measured, however, the level of marrow reactiveoxygen species was similar in the two groups, raising questions about their role in the

process of apotosis ( Matthes et al, 2000 ). Short half-life makes reactive oxygen species

notoriously difficult to assess. Further investigation should shed new light on the issues of bone marrow injury and ineffective erythropoiesis in sideroblastic anaemia.

Hereditary sideroblastic anaemiasX-linked sideroblastic anaemia

In 1945, Thomas Cooley described the first cases of X-linked sideroblastic anaemia intwo brothers from a large family in which the inheritance of the disease was documentedthrough six generations ( Cooley, 1945 ). Although rare, the disorder nonetheless is the mostcommon of the hereditary sideroblastic anaemias. Defects involving two independentgenes on the X-chromosome produce X-linked sideroblastic anaemia. The more commonform results from mutations of the gene encoding ALAS-2 ( Bottomley et al, 1995 ).
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Missense mutations of the ALAS-2 gene produce most cases of X-linked sideroblasticanaemia ( Bottomley et al, 1992; Cotter et al, 1992b; Cox et al, 1992, 1994; Edgar et al, 1997 ). Years after their initial evaluation, investigators located several members of the pedigree originallydescribed by Cooley and analysed their DNA using current techniques in molecular

biology ( Cotter et al, 1994 ). These family members did indeed have missense mutations

involving the ALAS-2 gene. Rarely has anyone correctly described two major disordersthat withstood the rigours of subsequent scientific investigation by more powerfulanalytical tools. The other disorder in this instance is, of course, Cooley's anaemia, nowknown as [beta]-thalassaemia major ( Cooley et al, 1927 ).

The mutations of the ALAS-2 gene can be classified according to their effects on theenzyme product: low affinity for pyridoxal phosphate, structural instability, abnormalcatalytic site, or increased susceptibility to mitochondrial proteases. Any of theseabnormalities decrease the biosynthesis and/or steady-state level of ALAS andconsequently lower production of protoporphyrin and haem. The degree of anaemiaimproves with pyridoxine supplementation when the mutation disrupts the catalyticassociation between ALAS-2 and pyridoxal phosphate ( Cox et al, 1994 ). Improvement in theanaemia could reflect enhanced protoporphyrin and haem synthesis with reducedmitochondrial iron deposition and dampened generation of reactive oxygen species.

The bone marrow of many patients with sideroblastic anaemia displays erythroidhyperplasia, consistent with the concept of ineffective erythropoiesis in this condition.The bone marrow's plethora of erythroid precursors fails to supply the peripheral bloodwith mature erythrocytes, making erythropoiesis by definition ineffective. Ineffectiveerythropoiesis increases iron absorption from the gastrointestinal tract. Therefore, patientswith even mild sideroblastic anaemia can develop substantial iron overload ( Fitzcharles et al,1982; Peto et al, 1983 ).

Hereditary x-linked sideroblastic anaemia usually occurs in males, of course. Casesinvolving females in a family derive most commonly from skewed lyonization patterns inthe affected girls ( Seip et al, 1971; Buchanan et al, 1980; Seto et al, 1982; Dolan & Reid, 1991 ). Somewomen in affected families have developed sideroblastic anaemia later in life owing to

progressive stochastic inactivation over time of the X-chromosome bearing the normalALAS-2 gene ( Cazzola et al, 2000 ).

A second group of hereditary X-linked sideroblastic anaemias result from defectsinvolving a different gene on the X-chromosome and manifest a strikingly different

phenotype. The syndrome produces a severe congenital ataxia, in addition to sideroblasticanaemia. The causal gene encodes an ATP-binding cassette (ABC) protein nowdesignated as hABC7 ( Shimada et al, 1998 ). The gene localizes to chromosome Xq13.1-q13.3 ( Raskind et al, 1991 ). ABC proteins generally mediate transmembrane transport of various small molecules. hABC7 is an orthologue of the yeast ATMl gene whose productlocalizes to the inner mitochondrial membrane ( Shimada et al, 1998 ).

A family with X-linked sideroblastic anaemia and ataxia displayed a mutation in thehABC7 gene that segregated with the affected males in the kindred and was absent incontrols ( Allikmets et al, 1999 ). The hABC7 gene in another family contained a singlemissense mutation that reduced the protein's functional activity by half, as assessed by

complementation studies using yeast in which the ATMl gene was deleted ( Bekri et al,2000 ). The complementation assay involved maturation of proteins containing an
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iron/sulphur (Fe/S) cluster. The investigators hypothesized that impaired production of Fe/S cluster proteins in erythroid precursors, such as IRP1, could produce sideroblasticanaemia. The ataxia could reflect dysfunction of cytoplasmic proteins crucial to spino-cerebellar development.

Other hereditary forms of sideroblastic anaemia

Reports exist of both autosomal dominant and autosomal recessive modes of transmissionfor hereditary sideroblastic anaemia ( Kasturi et al, 1982; Van Waveren et al, 1987; Jardine et al, 1994;Kardos et al, 1996 ). The genes involved in these cases remain elusive. Some investigators

postulate that the products of the affected genes somehow dampen the biosynthesis or theactivity of ALAS with a consequent diminution of haem production. ALAS is synthesizedon cytoplasmic ribosomes as a 65-kDa proenzyme whose leader mediates entry into themitochondrion ( Ferreira & Gong, 1995 ). The pro-sequence is clipped, producing a 595-kDaactive enzyme. Scission of the pro-sequence in the cytoplasm could produce sideroblasticanaemia. The enzymatically active ALAS in this scenario could not enter themitochondria. Furthermore, ALAS in the cytoplasm would be a target for many proteases.Hypercatabolism of ALAS appears to cause some cases of pyridoxine-response anaemia(Aoki et al, 1979 ). More information on the interplay between ALAS subcellular localizationand sideroblastic anaemia would broaden our understanding of this area.

Mitochondrial cytopathies

Oxidative phosphorylation within mitochondria generates most of the ATP used byeukaryotic cells. The mature erythrocyte is the sole mammalian cell devoid of mitochondria, relying totally on glycolysis as an energy source. Most cells contain

between 100 and 300 mitochondria ( Jaussi, 1995 ). These semiautonomous organelles probably began as freestanding prokaryotes that invaded eukaryotic cells more than a billion years ago ( Jansen, 2000 ). They eventually evolved a symbiotic relationship with their eukaryotic hosts. The former prokaryotes lost the capacity for independent existence but

became indispensable to the eukaryotic cells.

Mitochondria retain vestiges of their former independent life. Most importantly, theorganelles have a small DNA genome (about 16 kb) and replicate independently withintheir host cells. Mitochondrial DNA retains many features of prokaryotic genomes,including a circular structure lacking introns ( Boore, 1999 ). The mitochondrial genomeencodes a small number of proteins as well as several transfer RNA molecules.

Mitochondrial DNA lacks chromatin and the organelles have limited DNA repair capacity(Higuchi & Linn, 1995 ). Consequently, mutations in the mitochondrial genome that producesideroblastic anaemia probably remain uncorrected.

Mitochondria replicate independently of the nuclear genome ( Kuroiwa, 2000 ). When cellsundergo mitosis, the organelles distribute stochastically to the daughter cells. Acquiredmitochondrial defects therefore pass unevenly to the daughter cells. This property isimportant to some of the hereditary mitochondrial disorders that produce sideroblasticanaemia. This characteristic also poses a conundrum with respect to the acquiredsideroblastic anaemias. A few cases of sideroblastic anaemia associated withmyelodysplasia have acquired mutations that impair function of some cytochromes (see

below). The mutation presumably began as an alteration in a single mitochondrion. Themystery is how mitochondria with impaired enzymatic function come to predominate in
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the cells. Each mitochondrion has several genomes (i.e. several circular DNA molecules)and each cell has several hundred mitochondria. Logically, a defective mitochondrionshould be at a survival disadvantage. The acquired sideroblastic anaemias remind us thatmuch remains to be learned about the physiology of these fascinating organelles.

The mitochondrial cytopathies are a heterogeneous group of disorders produced bydeletions in the mitochondrial genome ( Egger et al, 1981; Kitano et al, 1986; Runge et al, 1986 ).Some deletions encompass as much as 30% of the 16-kb mitochondrial genome. Twofactors contribute to the peculiar inheritance patterns in these disorders. First, independentmitochondrial replication combined with random segregation into the daughter cells atmitosis means that, by pure chance, newly replicated cells can have more or fewer defective mitochondria. Second, mitochondrial cytopathies are maternally transmitted

because ova are the sole source of an embryo's mitochondria. A mother with mildmanifestations of a syndrome can thus have one child who is unaffected and another whohas extremely severe disease (mitochondrial heteroplasmy).

Pearson et al (1979 ) described children from several unrelated families who manifestedsideroblastic anaemia and exocrine pancreatic dysfunction. Subsequent cases of what isnow called Pearson's syndrome also had varying degrees of lactic acidosis, hepatic andrenal failure. Bone marrow examination showed, in addition to prominent ringsideroblasts, large vacuoles in the erythroid and myeloid precursors. Few of the probandssurvived past early childhood.

The disorder results from mitochondrial DNA deletions that often are as large as 4 kb(Cormier et al, 1990 ). Southern blots of mitochondrial DNA show genomes of normal sizealong with the truncated DNA. Variation in the intensity of the two bands reflectsmitochondrial heteroplasmy in the mother and offspring ( Bernes et al, 1993 ). These deletionsimpair the biosynthesis of various components of the mitochondrial respiratory chaincritical to mitochondrial function. Other disorders result from deletions of different

portions of the mitochondrial genome [e.g. myopathy, encephalopathy, ragged red fibres(in muscles) and lactic acidosis, or MERRL] ( Egger et al, 1981 ). Although sideroblasticanaemia is not in the clinical spectrum of most such syndromes, exceptions exist ( Inbal etal, 1995 ).

Wolfram syndrome is an instructive condition that could shed additional light on theinterplay between nuclear genes and mitochondria ( Borgna-Pignatti et al, 1989 ). The conditionresults from large deletions of the mitochondrial genome. The heteroplasmic nature of the

mitochondrial defect in Wolfram syndrome is typical of a mitochondrial cytopathy.

The defining characteristics of the disorder are diabetes insipidus, diabetes mellitus, opticatrophy and deafness (DIDMOAD). Sideroblastic anaemia in association withmitochondrial deletions occurs in a subset of these patients ( Rotig et al, 1993 ). Wolframsyndrome differs from other mitochondrial cytopathies by way of its autosomalinheritance pattern ( Barrientos et al, 1996 ).

Mutations in the gene designated WFS1/wolframin produce the DIDMOAD constellationof defects ( Inoue et al, 1998; Strom et al, 1998 ). The gene product is a transmembrane protein of undetermined function ( Takeda et al, 2001 ). Patients with defects in the WFS1/wolframin

gene do not necessarily develop sideroblastic anaemia in addition to the DIDMOADanomalies ( Hardy et al, 1999 ). Mutations in WSF1/wolframin could be necessary, but not
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sufficient to produce sideroblastic anaemia. The low incidence of both Wolframsyndrome and mitochondrial cytopathy makes coincidence unlikely in the subset of Wolfram patients who develop sideroblastic anaemia. Clearly, Wolfram syndrome isfertile ground in the search for links between the function of nuclear genes and themitochondrion.

Acquired sideroblastic anaemias

Acquired sideroblastic anaemias substantially exceed hereditary forms in frequency. Thedisorder sometimes surfaces in the context of a myelodysplastic syndrome. Other instances of acquired sideroblastic anaemias reflect exposure to toxins or deficiencies of nutritional factors. The heterogeneity of the hereditary sideroblastic anaemias can producecases with mild or moderate anaemia and varying degrees of iron overload ( French & Jacobs,1976; Fitzcharles et al, 1982; Peto et al, 1983 ). Some of these cases evade detection untiladulthood. Hereditary sideroblastic anaemias most often have striking phenotypes thatmanifest in childhood or infancy, however. In contrast, the acquired sideroblasticanaemias, particularly those associated with myelodysplasia, nearly always occur in older adults.

Myelodysplastic syndromes

The myelodysplasias are a group of disorders whose emblematic feature ishaematopoietic stem cell dysfunction ( Basa, 1992 ). Chromosomal abnormalities, such asthe 5q - anomaly, often accompany the condition ( Sole et al, 2000 ). All three haematopoieticcell lines display dysplastic features. Common characteristics include prominent nucleoli,abnormal granulation of myeloid precursors, multinucleated erythroid precursors and

small megakaryocytes that often contain a single nucleus. Ineffective erythropoiesis isfrequent ( Matthes et al, 2000 ). Deteriorating bone marrow function manifests as peripheral blood cytopenias of the three haematopoietic cell lines. Myelodysplasia has 1- and 5-year cumulative risks of acute leukaemia of 20% and 38% respectively ( Sole et al, 2000 ).

The abnormal stem cells can evolve a number of metabolic disturbances, includingdefective anchoring of phosphotidylinositol-linked membrane proteins (i.e. paroxysmalnocturnal haemoglobinuria, PNH), haemoglobin H production and ring sideroblasts ( Yooet al, 1980; Peters et al, 1983; Hillmen & Richards, 2000 ). Investigators often viewed the acquiredsideroblastic anaemia associated with myelodysplasia as a monolithic entity, dubbedrefractory anaemia with ring sideroblasts (RARS). Closer inspection revealed that certain

morphological and chromosomal features predict significant differences in the clinicalcourse of patients with sideroblastic anaemia ( Gattermann et al, 1990 ).

One subset of patients has dysplastic features confined to the erythroid series.Chromosomal abnormalities occur, but usually are relatively selective with defects suchas the 5q - anomaly. This condition is designated pure sideroblastic anaemia (PSA). Inthe absence of myeloid or platelet abnormalities, anaemia dominates the clinical course.The need for frequent transfusion produces iron overload that can impair cardiac functionand injure the liver. With adequate chelation therapy, these patients can survive and eventhrive for many years. Most importantly, acute leukaemia occurs rarely ( Germing et al, 2000 ).

The second group of patients has abnormalities in all three cell lines in addition to ringsideroblasts ( Balduini et al, 1999 ). Conspicuous chromosomal abnormalities often include
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multiple deletions, trisomy or inversions. Although the anaemia is troublesome,neutrophil and platelet anomalies are the cardinal clinical problems. Infection is the mostcommon cause of death, reflecting both neutropenia and neutrophil dysfunction. Bleedingowing to thrombocytopenia and/or platelet dysfunction is common. Nearly 40% of

patients who survive these problems develop an acute leukaemia that often is refractory to

treatment ( Sole et al, 2000 ). The prognostic implications of these two forms of sideroblasticanaemia associated with myelodysplasia require mandatory detailed morphological andcytogenetic evaluation at the time of diagnosis ( Yunis et al, 1988 ).

The ring sideroblasts associated with myelodysplastic syndromes manifest in both theearly and late erythroid precursors. This contrasts with the hereditary X-linked conditionsin which prominent sideroblastic rings generally appear in the more differentiatednormoblasts. Only recently have investigators pinpointed some of the abnormalities thatmight explain the ring sideroblasts associated with myelodysplasia. The greatestlikelihood is that multiple defects exist, reflecting the heterogeneous nature of myelodysplasia and its associated sideroblastic anaemia ( Gattermann, 2000 ).

Gattermann et al (1997 ) described at least two point mutations in mitochondrial DNA of patients with acquired sideroblastic anaemia. One mutation was a T->C change atnucleotide 6742 of the mitochondrial genome. The affected gene encodes cytochrome coxidase subunit 1. The mutation produced an aberrant protein in which a threonineresidue replaced isoleucine at position 280. The other mutation also involved a T->Ctransition, this time at nucleotide 6721 of the mitochondrial genome. The defect againaltered cytochrome c oxidase subunit 1, resulting in a change from methionine tothreonine at residue 273.

Mitochondria from other tissues of these patients showed no abnormality, consistent withan acquired defect solely involving the haematopoietic stem cells. Further investigation

proved these mutations to be heteroplasmic, i.e. the affected cells have a mixture of normal and mutant mitochondria. These investigators reported another mitochondrialDNA mutation involving one of the mitochondrial transfer RNAs ( Gattermann et al, 1996 ).The functional consequence, if any, of the mutation is unknown.

Drug- and toxin-induced sideroblastic anaemias

Drugs and toxins are important causes of sideroblastic anaemias and Table I lists some of the causal agents. The compounds most commonly implicated inhibit steps in the haem

biosynthetic pathway. Eliminating the offending agent usually corrects the sideroblasticanaemia. Ethanol is the most frequent cause of toxin-induced sideroblastic anaemia(Lindenbaum & Roman, 1980; Larkin & Watson-Williams, 1984 ). The complication is uncommon,

but the use (and misuse) of the agent is widespread. Ethanol probably causes sideroblasticanaemia by two mechanisms: direct antagonism to pyridoxal phosphate and/or associateddietary deficiency of this compound ( McColl et al, 1980; Middleton, III, 1986; Leibman et al, 1990 ).The bone marrow changes associated with ethanol toxicity include vacuoles in thenormoblasts in addition to sideroblasts. Interestingly, chloramphenicol commonly

produces vacuoles in the normoblasts and likewise can induce sideroblastic anaemia ( Beck et al, 1967 ).

Chloramphenicol inhibits mRNA translation by the 70S ribosomes of prokaryotes. Thedrug does not affect 80S eukaryotic ribosomes. Most mitochondrial proteins are encoded
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by nuclear DNA and are imported into the organelles from the cytosol where they aresynthesized. Mitochondria retain the capacity to translate, on their own ribosomes, a few

proteins encoded by the mitochondrial genome. True to its prokaryotic heritage,mitochondrial ribosomes are similar to those of bacteria, meaning that chloramphenicolinhibits protein synthesis by these ribosomes. Chloramphenicol-induced sideroblastic

anaemia is believed to result from this inhibition. Animal studies have documenteddiminished ALAS and ferrochelatase activity in cases of sideroblastic anaemia secondaryto chloramphenicol intoxication ( Rosenberg & Marcus, 1974 ).

More recently, Leiter et al (1999 ) examined the effects of chloramphenicol on cellular ironmetabolism using the human erythroleukaemia cell line, K562 as a model system. Asexpected, chloramphenicol inhibited oxidative metabolism, reduced the activity of cytochrome c oxidase and lowered the ATP content of the cells. Chloramphenicol alsomarkedly reduced the production of ferritin and the transferrin receptor by the cells. Thiseffect was surprising as the two iron-related proteins are synthesized on eukaryoticribosomes in the cytosol. Chloramphenicol did not inhibit the synthesis of other cytoplasmic or membrane proteins of the cell. The investigators concluded that the

previously unsuspected link between mitochondrial function and cellular iron metabolismmight contribute to the microcytic, hypochromic anaemia that often develops withchloramphenicol therapy even in the absence of sideroblastic changes in the bonemarrow.

Isoniazid frequently causes sideroblastic anaemia ( Sharp et al, 1990 ). Pyridoxine prophylaxisis part of treatment regimens involving the drug in order to prevent this complication.Isoniazid-induced sideroblastic probably reflects inhibition of ALAS activity ( Haden, 1967;Yunis & Salem, 1980 ).

Lead intoxication is a particularly insidious cause of anaemia ( Goyer, 1993 ). Although leadtoxicity is commonly mentioned as a cause of sideroblastic anaemia, no well-documentedcase exists in the literature. The assertion that lead produces sideroblastic anaemiaappears to be preserved in the literature by reference to indirect sources.

Finally, overdose of chelators such as penicillamine or triethylene tetraminedihydrochloride (Trientene or TTH) used to treat Wilson's disease can producesideroblastic anaemia. Excessive chelation produces a relative copper deficiency ( Perry etal, 1996 ). Wilson's disease is uncommon, so the use and availability of these copper chelators is low.

Nutritional factors

Nutrients involved in haem biosynthesis include pyridoxine and copper, among others.The role of pyridoxal phosphate, a metabolite of pyridoxine, has been mentioned. Primary

pyridoxine deficiency, usually secondary to malnutrition, is occasionally associated withsideroblastic anaemia. However, other manifestations, such as peripheral neuropathy anddermatitis, dominate the clinical picture. Pyridoxine deficiency frequently co-exists withalcoholism in cases of sideroblastic anaemia ( Hines & Cowan, 1970; Pierce et al, 1976 ).Although sideroblastic anaemia solely as a result of pyridoxine deficiency occurs inanimals, the phenomenon is undocumented in humans.
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The role of copper in human iron metabolism is extremely complex ( Danks, 1986 ). Copper enhances intestinal iron absorption, modulates reticuloendothelial activity, facilitatescellular iron uptake from transferrin and promotes iron incorporation into haem. Copper deficiency of all causes (malnutrition, prolonged total parenteral nutrition, gastric surgery,

prematurity, zinc supplementation, excessive chelation) can produce acquired

sideroblastic anaemia ( Ashkenazi et al, 1973; Zidar et al, 1977; Broun et al, 1991; Perry et al, 1996. )

Clinical manifestations and diagnosis

Sideroblastic anaemias tend to be moderate to severe conditions with haemoglobin levelsranging usually from 4 to 10 g/dl. Patients have the usual symptoms of anaemia includingfatigue, dizziness and decreased tolerance to physical activity. Other symptoms and signsnot related to anaemia can point to a cause of the condition (e.g. alcoholism).

The history should include detailed questions concerning possible toxin or drugexposures, as these conditions are reversible. A thorough family history looking for anaemia, particularly in male relatives, is important. Severe hereditary sideroblasticanaemias present in childhood. However, milder cases of hereditary sideroblastic anaemiawhose symptoms do not draw attention can elude detection until adulthood ( Fitzcharles et al,1982 ). Severe forms of most diseases are usually described first. Over time, a broader clinical spectrum with mild or formes frustes of the conditions becomes apparent. No

pathognomonic physical finding exists for sideroblastic anaemia.

The bone marrow picture in sideroblastic anaemia was described earlier. The blood smear sometimes reveals basophilic stippling, hypochromia and microcytosis, althoughnormocytosis and macrocytosis are possible, particularly in myelodysplastic syndromes.

Pappenheimer bodies are atypical except with absent splenic function. A dimorphic redcell population is characteristic of female carriers of the hereditary conditions. Patientswith pure sideroblastic anaemia or refractory anaemia with ring sideroblasts can alsomanifest a dimorphic red cell population ( Harris et al, 1993 ). Co-existence of normal andsideroblastic erythroid maturation is the probable basis of this phenomenon. Electronic

blood analysers display this anomaly as an elevated RDW.

Iron deficiency and sideroblastic anaemia can co-exist. This scenario is particularlycommon in patients with myelodysplasia who can have chronic gastrointestinal bleedingowing to platelet problems. Iron deficiency can mask the characteristic bone marrowfindings of sideroblastic anaemia. Sideroblastic anaemia remains in the differential

diagnosis of patients with iron deficiency and anaemia that is refractory to ironreplacement. A repeat bone marrow following iron replacement can show ringsideroblasts not seen in the initial sample.

Iron overload occurs far more frequently than does iron deficiency, even in the absence of transfusions. Tissue damage from the iron overload is an important cause of morbidityand mortality in these patients ( Schafer et al, 1985 ). Treatment with the iron chelator,desferrioxamine, can be life saving in patients who develop iron overload. Closemonitoring of the indirect indicators of tissue iron content is key to the management of these patients (see below).

Co-existing mutations in the gene responsible for hereditary haemochromatosis (HFE)appear not to be the basis of iron overload in sideroblastic anaemia ( Beris et al, 1999 ).
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Ineffective erythropoiesis with enhanced gastrointestinal iron absorption probablycontributes to iron overload in many patients ( Peto et al, 1983 ). The marked variability in theaetiology and bone marrow manifestations of sideroblastic anaemia could explain muchof the heterogeneous iron loading in this syndrome. The clinical picture parallels that seenwith congenital dyserythropoietic anaemias in which iron overload also correlates with

ineffective erythropoiesis and is not associated with the haemochromatosis gene mutation(Wickramasinghe et al, 1999 ). Levels of the soluble transferrin receptor correlate positivelywith iron overload in patients with congenital anaemias ( Cazzola et al, 1999 ). However,routine clinical assays such as serum ferritin levels and transferrin saturation usuallysuffice to detect iron overload in patients with sideroblastic anaemia.

Treatment

Treatment of sideroblastic anaemia begins with ruling out reversible problems includingalcohol or other drug toxicity, as well as exposure to toxins. Treatments are largelysupportive, consisting primarily of blood transfusions to maintain an acceptablehaemoglobin level. A trial of pyridoxine (100 mg/d orally) is reasonable as the drug hasfew drawbacks and is an enormous benefit in responsive cases ( Murakami et al, 1991 ). Withthe exception of some patients taking 1000 mg or more of pyridoxine daily, few side-effects have been reported. A complete response to pyridoxine generally occurs in casesresulting from ethanol abuse or the use of pyridoxine antagonists. Discontinuation of theoffending agent hastens recovery. Some patients with hereditary, X-linked sideroblasticanaemia also respond to pyridoxine ( Edgar et al, 1997 ). Improvement with pyridoxine is rarefor sideroblastic anaemias of other aetiologies.

After obtaining baseline parameters (red cell indices, iron studies), the initial dose of pyridoxine should be 50100 mg/d by mouth. Folic acid supplementation compensatesfor possible increased erythropoiesis, should the pyridoxine prove effective. Areticulocytosis occurs within 2 weeks in responsive cases, followed by a progressiveincrease in the haemoglobin level over the next several months. The maintenance dose of

pyridoxine is that which holds the haemoglobin level at a steady state. Microcytosis often persists, but is clinically insignificant.

Large doses of pyridoxine presumably overcome the defect in ALA production in patientswith low-activity mutant ALAS-2 enzymes. Investigation of one patient with pyridoxine-resistant X-linked sideroblastic anaemia showed that the mutant ALAS-2 protein wasunable to bind the beta subunit of ATP-specific succinyl CoA to form a functional

enzyme ( Furuyama & Sassa, 2000 ). Pyridoxine cannot compensate for an ALAS-2 mutantwith such extremely low activity. Correction of iron overload improves the response to pyridoxine in some patients with X-linked sideroblastic anaemia ( Cotter et al, 1999 ).

More recently, cytokine therapy with erythropoietin and granulocyte colony-stimulatingfactor (G-CSF) has been added to the treatment armamentarium for acquired sideroblasticanaemia. Combination therapy appears more effective than single-agent treatment ( Negrinet al, 1996 ). A large Scandinavian study with long-term follow-up showed a response ratein excess of 40% in patients with refractory anaemia and ring sideroblasts ( Hellstrom-Lindberg et al, 1998 ). Combination therapy with erythropoietin and G-CSF is particularlyappealing as side-effects are largely mild and other treatments are largely effete.
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Transfusion is the kernel of care with sideroblastic anaemias. Symptoms rather than anabsolute haemoglobin level or haematocrit should guide transfusion therapy. This limitsthe adverse consequences of transfusion, which include transmission of infections, allo-immunization and secondary iron overload.

Even in patients with no meaningful transfusion history, yearly monitoring of the ferritinlevel and transferrin saturation can unveil progressive iron loading. Iron chelation withdesferrioxamine is the standard treatment for iron overload, whether transfusional inorigin or the result of excessive iron absorption. Occasionally, patients with modestanaemia (e.g. haemoglobin = 10 g/dl) who are not transfusion dependent will toleratesmall-volume phlebotomies to remove iron. In some cases, the anaemia improves withremoval of excess iron ( French & Jacobs, 1976; Hines, 1976 ). This could reflect a reduction inmitochondrial injury by iron-mediated reactive oxygen species. This is speculation,however, and the scenario is distinctly unusual.

Case reports exist of allogeneic bone marrow or stem cell transplantation for inheritedsideroblastic anaemia ( Urban et al, 1992; Gonzalez et al, 2000 ). The obvious advantage is

possible cure, as has occurred in patients with [beta]-thalassaemia. Possible cure must be balanced against transplant complications, particularly in older people. Families withsevere forms of hereditary sideroblastic anaemia should receive genetic counselling.

Conclusion

Sideroblastic anaemias vary in aetiology and pathophysiology. The common thread inthese disorders is distinct biochemical abnormalities affecting the mitochondrion andhaem biosynthesis. Recent discoveries have improved our understanding of the interplay

between mitochondrial function, haem biosynthesis and cellular iron metabolism. Thisnew knowledge will probably point the way to improved therapies.

References

Allikmets, R., Raskind, W.H., Hutchinson, A., Schueck, N.D., Dean, M. & Koeller, D.M. (1999) Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Human Molecular Genetics , 8, 743749. Bibliographic Links [Context Link]

Amos, R.J., Miller, A.L. & Amess, J.A. (1988) Autosomal inheritance of sideroblastic anaemia. Clinical Laboratory Haematology , 10, 347353. Bibliographic Links [Context Link]

Aoki, Y., Muranaka, S., Nakabayashi, K. & Ueda, Y. (1979) delta-Aminolevulinic acid synthetase inerythroblasts of patients with pyridoxine-responsive anemia. Hypercatabolism caused by the increasedsusceptibility to the controlling protease. Journal of Clinical Investigations , 64, 11961203. [Context Link]

Ashkenazi, A., Levin, S., Djaldetti, M., Fishel, E. & Benvenisti, D. (1973) The syndrome of neonatal copper deficiency. Pediatrics , 52, 525533. Bibliographic Links [Context Link]

Balduini, C.L., Guarnone, R., Pecci, A., Centenare, E., Rosangela, I. & Ascari, E. (1999) The myelodysplasticsyndromes: predictive value of eight prognostic systems in 143 cases from a single institution. Haematolgica ,84, 1216. [Context Link]

Barrientos, A., Volpini, V., Casademont, J., Genis, D., Manzanares, J.M., Ferrer, I., Corral, J., Cardellach, F.,Urbano-Marquez, A., Estivill, X. & Nunes, V. (1996) A nuclear defect in the 4p16 region predisposes tomultiple mitochondrial DNA deletions in families with Wolfram syndrome. Journal of Clinical Investigations ,97, 15701576. Bibliographic Links [Context Link]
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