Albertine Donker

Rare Inherited Iron and Heme-related Anemias 117 3 Table 1. Continued 3C. X- linked sideroblastic anemia due to defects in ALAS2 Clinical presentation and diagnosis • XSLA due to an ALAS2 defect should be considered in patients of both gender and of all ages with pyridoxine responsive or unresponsive (mild) microcytic sideroblastic anemia with or without iron loading and in patients with unexplained iron loading. • In patients suspected for XLSA, iron parameters (ferritin, TSAT) should be checked to detect iron loading, as well as liver enzymes, and signs of liver fibrosis or hepatocellular carcinoma. • In case of elderly patients presenting with MDS-RARS or MDS-RCMD without specific cytogenetic abnormalities, the presence of ALAS2 defects should be considered, especially if the anemia is microcytic. Treatment • Management of patients with XLSA should involve treatment of anemia, and prevention and treatment of iron overload. • Initial treatment with pharmacological doses pyridoxine (50-200 mg/day) is recommended. Occasionally high doses (up to 300 mg/day) in heavy, active or elderly may be considered. • In case of pyridoxine responsiveness, lifelong supplementation of pyridoxine 10-100 mg daily is recommended. • Once a response is obtained evidence suggests the life-long maintenance dose may be lowered to 10-100 mg/day, since too high doses may give neurotoxicity. • Iron loading should be treated, preferably by phlebotomies. Family screening* • The proband should be informed about the X-linked inheritance pattern of anemia and/or iron overload due to ALAS2 defects. Brothers of the proband may be also affected. Sons of the proband are not affected. Daughters of the proband are obligate carrier of the relevant ALAS2 defect. • We recommend screening for the ALAS2 mutation: the brothers and also the mother, sisters and daughters (for carrier ship and for the reason that women may develop a XLSA phenotype later in life). The spouse should only be checked in case of consanguinity and reproductive age. • Female carriers and male hemizygous individuals should be screened for the XLSA phenotype.