Dominant inheritance of sialuria, an inborn error of feedback inhibition

"French type" sialuria, a presumably dominant disorder that, until now, had been documented in only five patients, manifests with mildly coarse facies , slight motor delay, and urinary excretion of large quantities ( >1 g/d) o f free N-acetylneuraminic acid (NeuAc). The basic defect consists of the ve ry rare occurrence of failed feedback inhibition of a rate-limiting enzyme, in this case uridinediphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimera se, by a downstream product, in this case cytidine monophosphate (CMP)-NeuA c. We report a new patient with sialuria who has a heterozygous G -->A subs titution in nucleotide 848 of the epimerase gene, which results in an R266Q change. The proband's other allele, as expected, had no mutation. However, the heterozygous R266Q mutation was detected in the patient's mother, who has similarly increased urinary levels of free NeuAc, thereby confirming, f or the first time, the dominant mode of inheritance of this inborn error. T he biochemical diagnosis of the proband was verified by the greatly increas ed level of free NeuAc in his cultured fibroblasts, the NeuAc distribution, mainly (59%) in the cytoplasm, and by the complete failure of 100 muM CMP- NeuAc to inhibit UDP-GlcNAc 2-epimerase activity in the mutant cells. These findings call for expansion of the phenotype to include adults and for mor e-extensive assaying of free NeuAc in the urine of children with mild devel opmental delay. The prevalence of sialuria is probably grossly underestimat ed.