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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1757-1769
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
Philip D. Cotter,
Alison May,
Liping Li,
A.I. Al-Sabah,
Edward J. Fitzsimons,
Mario Cazzola, and
David F. Bishop
From the Department of Human Genetics, Mount Sinai School of
Medicine, New York, NY; Department of Haematology, University of Wales
College of Medicine, Cardiff, UK; Department of Haematology, Western
Infirmary, Glasgow, Scotland; and Department of Internal Medicine and
Medical Oncology, University of Pavia and IRCCS Policlinico S. Matteo,
Pavia, Italy.
X-linked sideroblastic anemia (XLSA) in four unrelated male probands
was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new
mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid
substitutions Y199H, R411C, R448Q, and R452C. All probands were
clinically pyridoxine-responsive. The mutation Y199H was shown to be
the first de novo XLSA mutation and occurred in a gamete of the
proband's maternal grandfather. There was a significantly higher
frequency of coinheritance of the hereditary hemochromatosis (HH)
HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than
found in the normal population, indicating a role for coinheritance of
HFE alleles in the expression of this disorder. One proband
(Y199H) with severe and early iron loading coinherited HH as a C282Y
homozygote. The clinical and hematologic histories of two XLSA 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 supplementation. The proband with the R452C mutation was
symptom-free on occasional phlebotomy and daily pyridoxine. These
studies indicate the value of combined phlebotomy and pyridoxine
supplementation in the management of XLSA probands in order to prevent
a downward spiral of iron toxicity and refractory anemia.
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