Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing

Abstract

The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by the presence of ring sideroblasts in the bone marrow. X-linked sideroblastic anemia (XLSA) is caused by germline mutations in ALAS2. Hemizygous males have a hypochromic microcytic anemia, which is generally mild to moderate and is caused by defective heme synthesis and ineffective erythropoiesis. XLSA is a typical iron-loading anemia; although most patients are responsive to pyridoxine, treatment of iron overload is also important in the management of these patients. Autosomal recessive sideroblastic anemia attributable to mutations in SLC25A38, a member of the mitochondrial carrier family, is a severe disease: patients present in infancy with microcytic anemia, which soon becomes transfusion dependent. Conservative therapy includes regular red cell transfusion and iron chelation, whereas allogenic stem cell transplantation represents the only curative treatment. Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome characterized mainly by anemia attributable to ineffective erythropoiesis. The clinical course of RARS is generally indolent, but there is a tendency to worsening of anemia over time, so that most patients become transfusion dependent in the long run. More than 90% of these patients carry somatic mutations in SF3B1, a gene encoding a core component of the RNA splicing machinery. These mutations cause misrecognition of 3Ј splice sites in downstream genes, resulting in truncated gene products and/or decreased expression attributable to nonsense-mediated RNA decay; this explains the multifactorial pathogenesis of RARS. Variants of RARS include refractory cytopenia with multilineage dysplasia and ring sideroblasts, and RARS associated with marked thrombocytosis; these variants involve additional genetic lesions. Inhibitors of molecules of the transforming growth factor-␤ superfamily have been shown recently to target ineffective erythropoiesis and ameliorate anemia both in animal models of myelodysplastic syndrome and in RARS patients. Learning Objectives• To learn the 2 genes most commonly responsible for congenital sideroblastic anemia • To understand that X-linked sideroblastic anemia is an iron-loading anemia and that treatment of iron overload is at least as important as pyridoxine administration in the management of these patients • To understand that SLC25A38-mutant autosomal recessive sideroblastic anemia is a severe disease whose only curative treatment is allogenic hematopoietic stem cell transplantation • To describe the somatic mutations of RNA splicing machinery that are found in refractory anemia with ring sideroblasts and related myeloid neoplasms • To understand that SF3B1-mutant myelodysplastic syndrome represents a distinct entity • To describe the novel drugs that target ineffective erythropoiesis in patients with refractory anemia with ring sideroblastsThe sideroblastic anemias are a heterogeneous group of disorders characterized by anemia of varying severit...

Lethal ALAS2 mutation in males X‐linked sideroblastic anaemia

“…Miscarriages could have occurred in other previous small published families with females cases in which females are more numerous than males (Cotter et al, 1995;Cortesão et al, 2004;Ducamp et al, 2011). Moreover, a remarkable degree of heterogeneity in the X chromosome inactivation is frequently reported in XLSA (Cazzola & Malcovati, 2015), as it has also previously been described in Xlinked dominant lethal disorders (Franco & Ballabio, 2006). Our family study clearly indicates that investigation of excessive miscarriages in the pedigree of XLSA-affected females should be considered, and that the spectrum of the disease should be extended to include male lethal X-linked disorders.…”

Roles of Fe–S proteins: from cofactor synthesis to iron homeostasis to protein synthesis

“…Sideroblastic anemia is a hematologic syndrome characterized by iron accumulation in mitochondria of red cell precursors in the bone marrow leading to decreased viability of these precursors and anemia [12, 13]. Sideroblastic anemia reflects a problem with iron utilization for heme synthesis.…”

Missense variants in ALAS2 gene in five patients

“…ABCB7 , SLC19A2 , PUS1 , YARS2 , TRNT1 , mitochondrial DNA, and NDUFB11 genes are responsible so far for syndromic CSA (X‐linked SA with spinocerebellar ataxia, thiamine‐responsive megaloblastic anemia, myopathy with lactic acidosis and SA, B‐cell immunodeficiency with fevers and developmental delay, Pearson marrow‐pancreas syndrome). ALAS2, SLC25A38, GLRX5, STEAP3, and HSPA9 genes are responsible so far for nonsyndromic CSA (X‐linked SA or XLSA, autosomal recessive SA) …”

“…Anemia in many XLSA patients responds variably to supplementation with pyridoxine (vitamin B6) which is converted into pyridoxal 5‐phosphate (PLP), the active cofactor essential for ALAS2 activity. Due to elevated intestinal absorption of iron, patients will present parenchymal iron overload …”

“…ALAS2, SLC25A38, GLRX5, STEAP3, and HSPA9 genes are responsible so far for nonsyndromic CSA (Xlinked SA or XLSA, autosomal recessive SA). [1][2][3] XLSA, OMIM: 300751, is the most common type of nonsyndromic CSA and caused by variants in the erythroid-specific gene coding 5-aminolevulinate synthase (ALAS2) localized on chromosome Xp11.21. ALAS (EC 2.3.1.37) is the first enzyme of heme synthesis and catalyzes the condensation of glycine and succinyl coenzyme A into 5-aminolevulinic acid (ALA) in the mitochondria.…”