METABOLIC PERSISTENCE OF FETAL HEMOGLOBIN

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.