Page 943 - Williams Hematology ( PDFDrive )

918 Part VI: The Erythrocyte Chapter 59: Polyclonal and Hereditary Sideroblastic Anemias 919

ALA, a reaction mediated by ALA synthetase (Chap. 58). Furthermore, delivery to mitochondria (see Fig. 59–2). These studies also revealed
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pyridoxal phosphate is a factor in the enzymatic conversion of serine to that cytoplasmic iron not bound to transferrin is inefficiently used for
glycine (Chap. 41). This reaction generates a form of folate coenzyme heme biosynthesis and that the endosome–mitochondrion interaction
necessary for the formation of thymidylate, an important step in DNA increases chelatable mitochondrial iron. 87
synthesis. Pyridoxal 5′-phosphate, the active form of the coenzyme, An important distinction between erythroid and nonerythroid
must itself be enzymatically synthesized from pyridoxine. Deficiencies cells is the presence of a feedback mechanism in which “uncommitted”
in its biosynthesis have also been invoked as the possible cause of cer- heme inhibits iron acquisition from transferrin. 89–92 Although it is still
tain sideroblastic anemias, 27,69 but direct measurements of pyridoxal unresolved whether heme inhibits transferrin endocytosis 89,90 or iron
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kinase failed to confirm that the postulated lesion was present. 70 release from transferrin, the lack of heme plays an important role in
mitochondrial iron accumulation. Additionally, non–heme iron, which
Other Metabolic Defects and Acquired Associations with accumulates in erythroid mitochondria, cannot be released from the
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Sideroblastic Anemia of Uncertain Significance organelle unless it is inserted into heme. This finding suggests that
Increased levels of uroporphyrinogen 1 synthase are commonly mitochondria can release iron only when the metal is in a proper chem-
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encountered in patients with sideroblastic anemias. Alcohol, a com- ical form, in this case, inserted into protoporphyrin IX. These consid-
mon cause of secondary sideroblastic anemia, inhibits heme synthesis at erations provide framework to the pathogenesis of mitochondrial iron
several steps. Dramatically altered activity ratios of a wide diversity of accumulation in erythroblasts of patients with sideroblastic anemia
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enzymes have been described, 71,72 for example, elevated arginase activity. caused by ALAS2 defects, as well as those caused by agents inhibiting
Sideroblastic anemia has been found in a patient with apparent porphyrin biosynthesis (see Table 59–1).
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antibody-mediated red cell aplasia. There are alterations in red cell Of considerable interest, in 2014, Fleming and his coworkers
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antigen patterns frequently with an increase of i and a loss of A antigens demonstrated that mutations in an enhancer element in ALAS2 intron 1,
1
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(Chap. 136). Similar findings occur in certain hereditary and acquired which contains a GATA-binding site, cause a clinical phenotype similar
refractory anemias with cellular marrows but without ringed siderob- to patients with XLSA resulting from mutations in the ALAS2 coding
lasts. Such dyscrasias are also characterized by ineffective erythropoie- sequence itself.
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sis and, except for the lack of ringed sideroblasts, may in some instances A distinct form of XLSA, that associated with ataxia (XLSA/A),
be virtually indistinguishable from their sideroblastic counterparts. 75 was described in several families with putative mutations mapped to
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chromosome region Xq13. In contrast to ALAS2-linked disease, the
Pathogenesis of Ring Sideroblast Formation XLSA/A syndrome is associated with elevated erythrocyte protopor-
Iron accumulation within mitochondria is an unusual pathologic phe- phyrin IX levels. It was demonstrated that mutations of the ABCB7
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nomenon occurring only in erythroblasts of patients with sideroblastic gene is responsible for XLSA/A, and this was confirmed by other
anemias and, to a much lesser degree, in cardiomyocytes of patients reports. 52,94 The ABCB7 protein is thought to transfer iron-sulfur (Fe-S)
with Friedreich ataxia. 76,77 Mitochondrial iron accumulation has not clusters from mitochondria to the cytosol (Chap. 42). 76,95,96 How the
been demonstrated in patients with either primary or secondary iron disruption of Fe-S cluster export might impede heme biosynthesis is,
overload. The pathophysiology of ring sideroblast formation in patients however, not clear, but the accumulation of erythrocyte zinc–protopor-
with ALAS2 defects and those resulting from inhibitors of porphyrin phyrin IX is found in XLSA/A. 48,50,52 Additionally, mouse erythrocytes
biosynthesis (see Table 59–1) is likely because of the unique aspects with mutated (E433K) ABCB7 have an increase in zinc–protoporphyrin
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of the regulation of iron metabolism and heme synthesis in erythroid IX-to-heme ratios. Because the formation of zinc–protoporphyrin IX
cells (Chap. 58). These differences can account for the accumulation requires FECH, ABCB7 mutations cannot interfere with the activity of
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of non–heme iron in erythroid mitochondria of sideroblastic anemia this enzyme. Instead, the loss of function of ABCB7 may, by a yet-to-be-
patients. In hemoglobin-synthesizing cells, iron is specifically targeted defined mechanism, diminish the availability of reduced iron (the only
toward mitochondria that avidly take up iron even when the synthesis substrate of iron for FECH) required for the assembly of heme from
of protoporphyrin IX is suppressed (Chap. 58). 79–82 In contrast, non- protoporphyrin IX. In XLSA, as in ALAS2-associated sideroblastic ane-
erythroid cells store iron in excess of metabolic needs within ferritin. mia, decreased levels of heme likely contribute to the pathogenesis of
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Hence, erythroid-specific mechanisms and controls are involved in the ring sideroblast formation.
transport of iron into mitochondria in erythroid cells, but the nature of Another type of hereditary hypochromic anemia was described
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these processes, including the role of mitoferrin 1 (Chap. 42); an inner in shiraz (sir) zebra fish mutants. These mutants have a deficiency of
2+
mitochondrial membrane protein, which presumably provides Fe to glutaredoxin 5 (GLRX5) encoded by a gene (GLRX5) whose product
FECH, is poorly understood. The transferrin-bound iron is used for is required for Fe-S cluster assembly. This study demonstrated that the
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hemoglobin synthesis 78,82 with a high degree of efficiency and is targeted loss of the Fe-S cluster in the iron-regulatory protein 1 (IRP1) blocked
into erythroid mitochondria (Chap. 52), and because no intermediate ALAS2 translation by binding to the iron-responsive element (IRE)
for cytoplasmic iron transport has ever been identified in erythroid located in the 5′-untranslated region of ALAS2 mRNA. Subsequently,
cells, the following hypothesis of intracellular iron trafficking in devel- a case of GLRX5 deficiency in an anemic male with iron overload and a
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oping red cells has been proposed (see Fig. 59-2 from Chap. 52). This low number of ringed sideroblasts was reported. As in zebra fish with
model postulates that iron released from transferrin in the endosome shiraz mutants, ferritin levels were low and TfR levels were high in the
is passed directly from protein to protein until it reaches FECH, which patient’s cells; this can be explained by increased IRP1 binding to IREs
2+
incorporates Fe into protoporphyrin IX in the mitochondrion. Such in mRNAs of these two proteins. However, erythroblasts from zebra fish
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a transfer bypasses the cytosol, as the movement of iron between pro- shiraz mutants were not found to contain iron-loaded mitochondria.
teins could be mediated by a direct interaction of the endosome with
the mitochondrion. 78,86 The results of supporting experiments revealed Primary Acquired Sideroblastic Anemia (Refractory Anemia
that (1) iron, delivered to mitochondria via the transferrin–transferrin with Ring Sideroblasts—Myelodysplastic Syndrome)
receptor (TfR) pathway, is unavailable to cytoplasmic chelators 87,88 ; (2) The pathophysiology of acquired idiopathic sideroblastic anemias
transferrin-containing endosomes move to and contact mitochondria associated with myelodysplastic syndrome is distinct from the above
in erythroid cells; and (3) endosomal movement is required for iron discussed XLSAs. In these patients there is no evidence for a decrease

Kaushansky_chapter 59_p0915-0922.indd 918 9/17/15 3:17 PM