Sialuria is a rare inborn error of metabolism caused by excessive synthesis of
sialic acid (
N-acetylneuraminic acid, NeuAc). Fibroblasts cultured from the three known cases of
sialuria contained 70-200-fold increases in soluble
sialic acid, but normal concentrations of bound
sialic acid. The
sialic acid appeared in the cytosolic fraction of the cells on differential centrifugation, and was susceptible to
borohydride reduction, suggesting that accumulated
sialic acid was in the form of NeuAc and not
CMP-NeuAc. In biochemical studies,
CMP-NeuAc (50 microM) inhibited the
UDP-
N-acetylglucosamine (
UDP-GlcNAc) 2-epimerase of normal fibroblasts by 84-100%, but inhibited the
epimerase from
sialuria cells by only 19-31%. Feeding
sialuria cells up to 5 mM D-
glucosamine for 72 h increased free
sialic acid content 20-60%, but normal cells were unaffected by this treatment.
Cytidine feeding (5 mM, 72 h) reduced the NeuAc content of
sialuria cells, initially 112, 104, and 266 nmol/mg
protein, by 63-71 nmol/mg
protein;
CMP-NeuAc concentrations, initially 4, 2, and 5 nmol/mg
protein, increased by 14-33 nmol/mg
protein. Consequently, the total cellular content of soluble
sialic acid (NeuAc +
CMP-NeuAc) was lowered 14-46% by
cytidine feeding. The inheritance pattern of
sialuria has not been determined. However, cells from both parents of one
sialuria patient contained normal concentrations of free
sialic acid, and the parental
epimerase activity also responded normally to
CMP-NeuAc. We conclude that the basic biochemical defect in all known cases of
sialuria is a failure of
CMP-NeuAc to feedback-inhibit
UDP-GlcNAc 2-epimerase and
cytidine feeding can lower the intracellular soluble
sialic acid concentration of
sialuria cells.