Hereditary persistence of fetal hemoglobin (HPFH) has typically been a
scribed to mutations in the beta-globin gene cluster. Pharmacologic ag
ents, including the short-chain fatty acid butyrate, have been shown t
o upregulate fetal and embryonic globin gene expression. In this repor
t we investigate the possibility that metabolic derangements character
ized by an inability to metabolize another short-chain fatty acid, pro
pionate, could be associated with a persistence of fetal hemoglobin un
related to alterations in the beta-globin cluster. Embryonic globin ge
ne upregulation in a murine adult erythroid cell culture was shown by
RNase protection after induction with three short-chain fatty acids (C
-2-C-5). Chart reviews acid measurement of fetal hemoglobin in five pa
tients with abnormalities in propionate (C-3) metabolism were undertak
en; SSCP/dideoxy fingerprint analysis of the gamma-globin gene promote
rs was done in three of these five patients. Twelve patients with othe
r metabolic derangements served as controls. Only the four patients wi
th clinically severe abnormalities in propionate metabolism (ages 2 to
11), but without anemia, showed a sustained elevation in fetal hemogl
obin (3% to 10%). The level of elevation of fetal hemoglobin in these
patients, who lack erythropoietic stress, suggests that propionic acid
and/or its metabolites are potent stimulators of fetal hemoglobin exp
ression. Study of this group of patients should allow unique insights
into the longterm effects of sustained exposure to elevations of short
-chain fatty acid levels. (C) 1995 by The American Society of Hematolo
gy.