Anemia, Sideroblastic, 1

A number sign (#) is used with this entry because sideroblastic anemia-1 (SIDBA1) is caused by mutation in the gene encoding delta-aminolevulinate synthase-2 (ALAS2; 301300) on chromosome Xp11.

Description

The essential features of X-linked sideroblastic anemia include the following: (1) a hypochromic microcytic anemia and 2 discrete populations of red blood cells, one microcytic and the other normocytic; (2) marrow ringed sideroblasts, particularly prominent in the late erythroid precursors; (3) a variable hematologic response to pharmacologic doses of pyridoxine; and (4) systemic iron overload secondary to chronic ineffective erythropoiesis. The age of clinical onset of the disorder can vary from in utero to the ninth decade. Whereas males are preferentially affected, females may present with clinically severe anemia. More commonly, female carriers of the disease have an increased red blood cell distribution width and sometimes erythrocyte dimorphism (Fleming, 2002).

Genetic Heterogeneity of Sideroblastic Anemia

See also SIDBA2 (205950), caused by mutation in the SLC25A38 gene (610819) on chromosome 3p22; SIDBA3 (616860), caused by mutation in the GLRX5 gene (609588) on chromosome 14q32; and SIDBA4 (182170), caused by mutation in the HSPA9 gene (600548) on chromosome 5q31.

Clinical Features

X-linked sideroblastic anemia was first described by Cooley (1945), a Detroit pediatrician-hematologist who also first described thalassemia in a definitive way. He pointed out possible X-linkage in a family in which 19 males in 5 generations were affected, with transmission through unaffected females.

Rundles and Falls (1946) reported 2 families, 1 of which was the same as that reported by Cooley. Somewhat enlarged spleens and minor red cell abnormalities without anemia were observed in female carriers. Pyridoxine responsiveness was demonstrated in at least 2 affected members of Rundles and Falls' family (Bishop and Bethel, 1959; Horrigan and Harris, 1964).

Byrd and Cooper (1961) referred to the disorder as hereditary iron-loading anemia.

Bickers et al. (1962) described the disorder in a man whose mother, sister, and 5 children had hematologic involvement in various degrees. Losowsky and Hall (1965) described a remarkably extensively affected family with a typical X-linked recessive inheritance pattern with clinical expression in some presumed heterozygous females.

Associated hypolipidemia and hypocholesterolemia were pointed out by Spitzer et al. (1966).

Prasad et al. (1968) studied a black family segregating both sideroblastic anemia and G6PD deficiency (300908). In females doubly heterozygous in coupling, there was a correlation between small red cells and low G6PD.

Soslau and Brodsky (1989) described a 62-year-old male and his 30-year-old daughter with sideroblastic anemia. Both also had prolonged bleeding times with abnormalities of the platelets which appeared to represent a 'storage pool defect.' The sideroblastic anemia and the platelet abnormality may have been coincidentally associated.

Pyridoxine deficiency is prevalent in patients undergoing dialysis (Kopple et al., 1981). Furuyama et al. (2003) reported an 81-year-old man who developed sideroblastic anemia while undergoing hemodialysis, The diagnosis of sideroblastic anemia was established by the presence of ringed sideroblasts in the bone marrow, which were completely eliminated by treatment with oral pyridoxine. The very late onset in this case of XLSA emphasized that nutritional deficiencies caused either by dietary irregularities in the elderly or, as in this case, by maintenance hemodialysis therapy, may uncover occult inherited enzymatic deficiencies in the heme biosynthetic pathway. Genetic analysis identified a mutation in the ALAS2 gene (D159N; 301300.0012).

Heterozygous Females

Peto et al. (1983) focused attention on iron overload in mild sideroblastic anemia after the death from cardiac iron loading of a middle-aged woman with a very mild form of familial sideroblastic anemia. Their studies demonstrated that iron overload can occur without severe anemia, most likely resulting from excessive absorption of dietary iron. Several additional patients had familial disease; mother and 2 sisters, mother and son, and 2 brothers were affected. None of the 5 patients tested showed linkage to the locus for hemochromatosis (235200). Peto et al. (1983) concluded that in heterozygous females 'even a minor population of hypochromic peripheral red cells may be important.'

Cotter et al. (1995) described a previously unaffected 81-year-old woman in whom microcytic sideroblastic anemia developed. The initial diagnosis was myelodysplastic syndrome, but the recognition of the X-linked congenital sideroblastic anemia allowed successful treatment with pyridoxine. She was found to be heterozygous for a point mutation of the ALAS2 gene (301300.0005).

There is evidence from other sources that skewed lyonization can be an acquired pattern. In the study of peripheral blood leukocytes by Busque et al. (1996), the incidence of skewing was 1.9% in neonates, 4.5% in women who were 28 to 32 years old, and 22.7% in women who were 60 years of age or older. Cazzola and Bergamaschi (1998) estimated that in 30 to 40% of elderly women, hematopoietic cells (erythroid cells, granulocytic cells, monocytes, and megakaryocytes) have more than 90% expression of 1 parental X chromosome. Puck and Willard (1998) reviewed mechanisms for a skewed pattern of X inactivation with a diagram of 3 different mechanisms.

Aivado et al. (2006) reported a family in which a mother and her 2 daughters had pyridoxine-unresponsive sideroblastic anemia confirmed by genetic analysis. The disorder was variable in severity and X-chromosome inactivation studies were done. The mother developed progressive anemia in the fifth decade as she acquired an age-related nonrandom X-inactivation in hematopoietic cells. One daughter, with a mild phenotype at age 31, had moderate constitutive skewing of X-chromosome inactivation, and the other daughter, who was severely affected with clinical onset at age 16, had extreme constitutive skewing of X inactivation. There was also random X inactivation in reticulocytes of all 3 women that contrasted with a markedly skewed inactivation pattern in bone marrow erythroid cells. This discordance was attributed to apoptosis of erythroid precursors derived from progenitor cells with an active X-chromosome bearing the ALAS2 mutation.

Biochemical Features

Pinkerton (1967) observed 2 morphologically distinct populations of cells in heterozygotes. In a heterozygote, Lee et al. (1968) separated 2 populations of red cells by centrifugation in layered gum acacia solutions of different specific gravity. They found that the microcytes had a lower level of free protoporphyrin than did the normal cells, but unimpaired capacity to convert delta-aminolevulinic acid to protoporphyrin, suggesting a defect at or before the step in which delta-aminolevulinic acid is synthesized.

Hines (1971) observed decreased levels of pyridoxal phosphokinase in red cells and livers of patients with pyridoxine-dependent refractory sideroblastic anemia.

Aoki et al. (1973) found deficiency of delta-aminolevulinic acid synthetase in the red cells of patients with sideroblastic anemia, some of whom were males with congenital anemia which in some responded to treatment with B6.

Aoki et al. (1979) found an apparent increase in proteolytic sensitivity of erythroblast ALAS in 2 patients with pyridoxine-responsive anemia.

Clinical Management

Paradoxically, phlebotomy is effective treatment for this form of anemia and can be done especially when there is a satisfactory response to pyridoxine. As in genetic hemochromatosis, the main objective is to prevent the development of diabetes, cirrhosis, and heart failure from iron overload. Phlebotomy must be done with more caution than in genetic hemochromatosis. Peto et al. (1983) noted that measures of erythroid expansion are useful in assessing risk of iron overload, and phlebotomy or iron-chelation therapy is indicated for prophylaxis.

Gonzalez et al. (2000) reported a case of pyridoxine refractory hereditary sideroblastic anemia in a 19-year-old man who underwent peripheral blood stem cell transplantation from his HLA-identical brother. By using short tandem repeat polymorphism, 100% donor cells were observed in peripheral blood on day +21; bone marrow showed mixed chimerism from day +21 to day +221, when 100% cells of donor origin were observed. The patient developed extensive chronic graft-versus-host disease (GVHD; see 614395) with favorable response to treatment. When the hemoglobin range was normal, a program of phlebotomies reduced serum ferritin levels. Three years after transplantation, the patient had completely normal hemoglobin values.

Molecular Genetics

In a male with a pyridoxine-responsive form of X-linked sideroblastic anemia, Cotter et al. (1992) identified a causative mutation in the ALAS2 gene (301300.0001).

In affected members of the original family with X-linked sideroblastic anemia described by Cooley (1945), Cotter et al. (1994) identified a missense mutation in the ALAS2 gene (301300.0003).

In each of 4 unrelated males with X-linked sideroblastic anemia, Cotter et al. (1999) identified mutations in the ALAS2 gene (see, e.g., 301300.0008). All probands were clinically pyridoxine-responsive. One mutation was found to be the first de novo XLSA mutation, having occurred in a gamete of the proband's maternal grandfather.

Genotype/Phenotype Correlations

In 18 unrelated XLSA hemizygotes, Cotter et al. (1999) found a significantly higher frequency of coinheritance of the hereditary hemochromatosis HFE mutant allele C282Y (613609.0001) than found in the normal population. One proband with the Y199H mutation (301300.0017) with severe and early iron loading was homozygous for C282Y. The clinical and hematologic histories of 2 XLSA probands suggested that iron overload suppresses pyridoxine responsiveness. Reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation (301300.0018) was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicated the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

Animal Model

The zebrafish mutant 'sauternes' (sau) has a microcytic, hypochromic anemia. During embryogenesis, sau mutants have delayed erythroid maturation and abnormal globin gene expression. Using positional cloning techniques, Brownlie et al. (1998) showed that sau encodes the erythroid-specific isoform of delta-aminolevulinate synthase, the enzyme required for the first step in heme biosynthesis. As mutations in ALAS2 cause congenital sideroblastic anemia in humans,

History

Weatherall et al. (1970) were unable to demonstrate lyonization of the Xg locus (314700) by observing 2 populations of cells in females heterozygous for familial sideroblastic anemia.

Several reports (see Sessarego et al., 1983) suggested a connection between chromosomal rearrangement involving a breakpoint at Xp13 and the development of idiopathic acquired sideroblastic anemia progressing to acute nonlymphocytic leukemia. Holmes et al. (1990) found no consistent cytogenetic abnormalities in X-linked sideroblastic anemia.