Issue: 2014 > May > original article

X-linked sideroblastic anaemia due to ALAS2 mutations in the Netherlands: a disease in disguise

A.E. Donker, R.A. Raymakers, H.K. Nieuwenhuis, M.J.H. Coenen, M.C. Janssen, M.A. MacKenzie, P.P.T. Brons, D.W. Swinkels


Background: X-linked sideroblastic anaemia (XLSA;
OMIM#300751) is the most common inherited form
of sideroblastic anaemia and is associated with several
mutations in the erythroid specific 5-aminolevulinate
synthase gene (ALAS2). This gene encodes for aminolevulinic acid synthase 2 (ALAS2), the catalytic enzyme involved in the first en rate-limiting step of haem biosynthesis.1-3 The disorder is characterised by mostly mild hypochromic microcytic anaemia with bone marrow ring sideroblasts. Even untransfused patients with mild or no anaemia are at risk for severe systemic iron overload due to ineffective erythropoiesis. To date, 61 different ALAS2 mutations have been reported in 120 families with XLSA. Descriptions of molecularly confirmed case series from the Netherlands, however, are lacking. Methods: We reviewed age of presentation, clinical and biochemical features, ALAS-2 defects and treatment
characteristics of 15 Dutch patients from 11 unrelated
families diagnosed with XLSA. Results and Conclusions: In one family a novel pathogenic c.1412G>A (p.Cys471Tyr) mutation was found. All other families shared the previously described c.1355G>A (p.Arg452His) mutation. Haplotype analysis in seven
probands with the p.Arg452His mutation strongly suggests that six of them were ancestrally related. Nevertheless, their phenotype was very different. Our patients illustrate the phenotypical heterogeneity in the presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the diagnosis, follow-up and treatment of the disease. A timely diagnosis avoids unnecessary investigations and allows adequate treatment
that can prevent systemic iron load with subsequent severe life-threatening complications. Therefore, we suggest considering XLSA in both male and female patients with unexplained iron overload and/or (mild) microcytic anaemia, also at older age.