PMID- 10029606
OWN - NLM
STAT- MEDLINE
DCOM- 19990318
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 93
IP  - 5
DP  - 1999 Mar 1
TI  - 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.
PG  - 1757-69
AB  - 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.
FAU - Cotter, P D
AU  - Cotter PD
AD  - Department of Human Genetics, Mount Sinai School of Medicine, New York, NY, USA.
FAU - May, A
AU  - May A
FAU - Li, L
AU  - Li L
FAU - Al-Sabah, A I
AU  - Al-Sabah AI
FAU - Fitzsimons, E J
AU  - Fitzsimons EJ
FAU - Cazzola, M
AU  - Cazzola M
FAU - Bishop, D F
AU  - Bishop DF
LA  - eng
GR  - R01 DK40895/DK/NIDDK NIH HHS/United States
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (DNA Primers)
RN  - EC 2.3.1.37 (5-Aminolevulinate Synthetase)
SB  - IM
MH  - 5-Aminolevulinate Synthetase/*genetics
MH  - Adolescent
MH  - Adult
MH  - Anemia, Sideroblastic/blood/*genetics
MH  - Child
MH  - DNA Primers
MH  - Female
MH  - Genetic Linkage
MH  - Hemochromatosis/blood/*genetics/therapy
MH  - Humans
MH  - Male
MH  - *Mutation
MH  - Phlebotomy
MH  - *X Chromosome
EDAT- 1999/02/25 00:00
MHDA- 1999/02/25 00:01
CRDT- 1999/02/25 00:00
PHST- 1999/02/25 00:00 [pubmed]
PHST- 1999/02/25 00:01 [medline]
PHST- 1999/02/25 00:00 [entrez]
AID - S0006-4971(20)48741-5 [pii]
PST - ppublish
SO  - Blood. 1999 Mar 1;93(5):1757-69.