title: Dominant inheritance of sialuria, an inborn error of feedback inhibition.
abstract: "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) of free N-acetylneuraminic acid (NeuAc). The basic defect consists of the very rare occurrence of failed feedback inhibition of a rate-limiting enzyme, in this case uridinediphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase, by a downstream product, in this case cytidine monophosphate (CMP)-NeuAc. We report a new patient with sialuria who has a heterozygous G-->A substitution 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, for the first time, the dominant mode of inheritance of this inborn error. The biochemical diagnosis of the proband was verified by the greatly increased level of free NeuAc in his cultured fibroblasts, the NeuAc distribution, mainly (59%) in the cytoplasm, and by the complete failure of 100 microM 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 more-extensive assaying of free NeuAc in the urine of children with mild developmental delay. The prevalence of sialuria is probably grossly underestimated.
authors.affiliation: Departments of Pediatrics and Medical Genetics, Ghent University School of Medicine, B-9000 Ghent, Belgium. juliaan.leroy@rug.ac.be
authors.forename: J G
authors.initials: JG
authors.lastname: Leroy
authors.forename: R
authors.initials: R
authors.lastname: Seppala
authors.forename: M
authors.initials: M
authors.lastname: Huizing
authors.forename: G
authors.initials: G
authors.lastname: Dacremont
authors.forename: H
authors.initials: H
authors.lastname: De Simpel
authors.forename: R N
authors.initials: RN
authors.lastname: Van Coster
authors.forename: E
authors.initials: E
authors.lastname: Orvisky
authors.forename: D M
authors.initials: DM
authors.lastname: Krasnewich
authors.forename: W A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D000328:Adult; D001483:Base Sequence; D002238:Carbohydrate Epimerases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003569:Cytidine Monophosphate N-Acetylneuraminic Acid / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D002658:Developmental Disabilities / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000652:urine; D029968:Escherichia coli Proteins; D005246:Feedback; D005260:Female; D005347:Fibroblasts; D005602:France; D005799:Genes, Dominant / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology / Q000652:urine; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D012794:Sialic Acids / Q000032:analysis / Q000652:urine*; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D012794:Sialic Acids; D003569:Cytidine Monophosphate N-Acetylneuraminic Acid; D014537:Uridine Diphosphate N-Acetylglucosamine; D002238:Carbohydrate Epimerases; C100033:UDP acetylglucosamine-2-epimerase; C083982:wecB protein, E coli