LAUSR

X-linked Sideroblastic Anaemia (XLSA, Mendelian Inheritance in Man reference 300751), the most common type of congenital sideroblastic anaemia (CSA), results from germline mutations in the erythroid-specific form of the 5-aminolevulinate synthase gene (ALAS2). ALAS2 is the first enzyme of the haem biosynthesis pathway and is essential to support haemoglobin synthesis. Affected males typically exhibit microcytic anaemia and iron deposits in the mitochondria of erythroid precursors (ring sideroblasts). Anaemia is generally mild and patients are rarely transfusion dependent. However patients could exhibit, with time, severe parenchymal iron overload due to intestinal hyper absorption of iron (Cazzola & Malcovati, 2015). Most of the ALAS2 mutations are missense mutations with partial loss-of-function alleles; mutations in a GATA transcription factor-binding in intron 1 of the ALAS2 gene have also been reported (Campagna et al, 2014). However penetrance and phenotypic expression of XLSA is highly variable, even in a same family(Cortes~ao et al, 2004; Aguiar et al, 2014). Up to one-third of female cases may be affected, mainly by skewed X-chromosome inactivation which increases with age (Ducamp et al, 2011); one case of macrocytic anaemia in a female with dominant mutation in ALAS2 without skewed X inactivation has also been reported to alter erythropoiesis through cell non-autonomous effects (Sankaran et al, 2015). We report for the first time in a very large, four-generation pedigree a new missense mutation in the ALAS2 gene inducing a Male Lethal X-linked syndrome ascertained through an adult heterozygous female with highly skewed X inactivation with a mild form of macrocytic CSA and an excessive number of miscarriages. The proposita of this non-consanguineous family (Fig 1A; Individual III.9) was a female of European ancestry. She exhibited an unexplained congenital, non-regenerative, macrocytic, moderate anaemia, (first assessment at 6 years old). Red blood cell (RBC) transfusions were required only twice during her pregnancy. She was diagnosed with CSA when aged 23 years. A complete blood count showed a nonregenerative macrocytic [mean cell volume (MCV) 107 fl] anaemia (Hb: 107 g/l)that was not dimorphic, with red cell distribution width (RDW) -SD 52 5 fl [normal range (N):