Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: Increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis

X-linked sideroblastic anemia (XLSA) in four unrelated male probands was ca used by missense mutations in the erythroid-specific 5-aminolevulinate synt hase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406 T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All p robands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the prob and's maternal grandfather. There was a significantly higher frequency of c oinheritance of the hereditary hemochromatosis (HH) HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indi cating a role for coinheritance of HFE alleles in the expression of this di sorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLS A probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementat ion. The proband with the R452C mutation was symptom-free on occasional phl ebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA proband s in order to prevent a downward spiral of iron toxicity and refractory ane mia. (C) 1999 by The American Society of Hematology.