Ask the Hematolgoist July-August 2006

A three-year-old Caucasian boy with normal growth and development was noted to have microcytic, hypochromic anemia at the age of nine months, prior to a minor surgical procedure. Hemoglobin thereafter ranged from 5.9 to 7.2 g/dL, MCV 44 to 52 fL, and RDW 28 to 32 percent; hemoglobin electrophoresis showed normal values of Hb A, A² , and F, and iron supplement was prescribed. At age two, blood iron studies revealed serum iron of 212 µg/dL, TIBC 210 µg/dL, and ferritin of 1053 µg/L without change in the hemogram. The iron therapy was discontinued and blood was submitted for research studies of "iron-related genes." The parents had requested a second opinion, and this hematologist discovered ring sideroblasts in the bone marrow aspirate. On subsequent pyridoxine supplementation there was no effect on the anemia. The blood count values of the parents and an older sister are normal. Mutation analysis of the erythroid 5-aminolevulinate synthase (ALAS² ) gene is pending.

Once iron deficiency or iron-deficient erythropoiesis (i.e., from chronic infection or inflammation) and a thalassemic phenotype have been excluded, congenital sideroblastic anemia is the third most common cause of microcytic anemia. To establish the diagnosis of the latter, appropriate iron staining of the bone marrow aspirate is essential.

X-linked sideroblastic anemia (XLSA) typically exhibits microcytic anemia in males. Severity as well as any response to pyridoxine is generally dictated by the nature of the mutation in the ALAS2 gene affecting the function of the ALAS2 enzyme, and the disorder may be discovered at any age. When an ALAS2 mutation is not found, the anemia can be attributed to an as-yet-undefined autosomal defect(s), with dominant or recessive inheritance, or it may be sporadic. All other diagnostic considerations involve sideroblastic anemia as a component of genetic syndromes. In the very rare syndrome of X-linked sideroblastic anemia with ataxia (XLSA/A), microcytic anemia has been mild in three reported families. The others, namely thiamine-responsive megaloblastic anemia, myopathy with lactic acidosis, and sideroblastic anemia (MLASA) and Pearson syndrome, have normal or macrocytic erythrocyte indices.

While isolated congenital or inherited sideroblastic anemia in males is almost always characterized by microcytic morphology, which essentially excludes MDS, XLSA expressed in females is usually normocytic or macrocytic. Most women carrying an ALAS2 mutation who develop the disorder in adulthood do so due to age-related nonrandom X-inactivation in hematopoietic tissue, with preferential inactivation of the normal X chromosome, and very rarely because of constitutive skewed X-inactivation. Thus examination of the X-inactivation status is useful for screening females with sideroblastic anemia caused by mutations in the ALAS2 gene. The lack of microcytosis in affected women is attributable to a markedly defective or non-functional mutant ALAS2 enzyme in apoptotic erythroid precursors, and the peripheral erythrocytes represent essentially only progeny of the residual normal clone that are released at an accelerated rate from the marrow.

Once a genetic basis for the sideroblastic anemia is established, the family or patient can be advised that there is no known increased risk for leukemia or the like in the disorder. It is also advisable to screen family members for silent disease.

The DNA analysis should establish whether the child has XLSA due to an ALAS2 mutation. Analysis of how an ALAS2 mutation affects the structure and function of the ALAS2 protein can predict a clinical response to supplements of its cofactor pyridoxine. Up to two-thirds of cases respond variably to pyridoxine supplementation, but the hemoglobin normalizes in only about one-third of responders. The vitamin is ineffective in all other forms of sideroblastic anemia.

Otherwise, treatments remain largely supportive. They can provide normal survival in many cases and are aimed at control of symptoms of anemia and prevention of organ damage from the associated iron overload. Red cell transfusion should be kept to a minimum. Phlebotomy or iron chelation therapy is generally instituted when serum ferritin is above 500 µg/L.

Cure of congential sideroblastic anemia when not associated with a genetic syndrome can only be achieved with hematopoietic stem cell transplantation save for the attendant risks of the procedure.