Abstract
Introduction: X-linked sideroblastic anemia (XLSA), a rare disease characterized by an inherited microcytic and hypochromic anemia with high ferritin serum level and dyserythropoiesis with ring sideroblasts in bone marrow (BM), caused by mutations in the erythroid-specific 5-aminolevulinic acid synthase (ALAS2) gene located in the X chromosome is usually diagnosed in the early age. Anemia is often mild and well tolerated with variable response to pyridoxine treatment. The evolution can be dominated by iron overload due to hyperabsorption of iron and transfusional uptake. We report 3 adult cases, diagnosed after 30 years old, of XLSA transfusion free with iron overload. Case 1: A 34 y-old man, was seen in 2005 for a microcytic anemia and high ferritin serum, hemoglobin (Hb) 10.4 g/dl, MCV 70 fl and MCH 20.9 pg, dyserythropoiesis with 36% of ring sideroblasts (RS) on BM, ferritin serum level 2284 ng/ml (N: 30–300), transferrin sat 93% (N: 17–40). The hepatic MRI revealed a major iron overload at 350 μmol/g (N < 36) confirmed by biopsy showing a slight liver fibrosis. Molecular analysis of ALAS2 gene demonstrates a p.Arg452Gly mutation. Pyridoxine treatment and phlebotomy allowed a correction of anemia and reduction of the S-ferritin (371 ng/ml). Case 2: The family investigation of case 1 detect an affected first cousin, a 38 y-old man with Hb 12.9 g/dl, MCV 77 fl and MCH 25 pg, S-ferritin 559 ng/ml and transferrin saturation 91%. BM aspirate showed a dyserythropoiesis with 20% of ring sideroblasts. The molecular analysis of ALAS2 gene found the same mutation. The MRI indicates a marked liver iron overload (150 μmol/g) and elastography measurement (Fibroscan®) no fibrosis. Treatment by pyridoxine and phlebotomy every 2 weeks allowed a favourable outcome. Case 3: a 46 y-old man presented in 1994 a microcytosis without anemia Hb 13,2 g/dl, MCV 68 fl and MCH 22,5 pg, S-ferritin 1000 ng/ml transferrin saturation 63% and dyserythropoiesis with 66% of ring sideroblasts on BM. Treatment by pyridoxine was not efficient and iterative phlebotomies because of asthenia with arthralgies attributed to iron overload, with benefit for the patient. The molecular analysis of ALAS2 gene revealed a p.Arg572His mutation.
Comments: Hereditary etiology due to ALAS2 gene mutations is a diagnostic rarely performed in adults, because of his rarity far behind primary acquired myelodysplastic syndromes (RARS) and secondary causes induced by drugs or toxics. The XLSA is the main cause of hereditary SA. More than 30 mutations have been identified. The 3 cases reported are XLSA due to 2 new ALAS2 gene mutations, never reported in the Human Gene Mutation Database.
Conclusion: In XLSA with ALAS2 gene mutation, anemia often moderate, well tolerate and often unrecognized. Iron overload appears in this disease without any transfusion. Early diagnosis allows preventing the complications of the iron overload by iterative phlebotomies or by chelators. Pyridoxine treatment is indicated with variable response.
Congenital sideroblastic anemia with a novel variant of the PUS1 gene mutation
