RESUMO
"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.
Assuntos
Carboidratos Epimerases/genética , Proteínas de Escherichia coli , Genes Dominantes/genética , Erros Inatos do Metabolismo/enzimologia , Erros Inatos do Metabolismo/genética , Ácidos Siálicos/urina , Adulto , Sequência de Bases , Carboidratos Epimerases/antagonistas & inibidores , Carboidratos Epimerases/metabolismo , Criança , Pré-Escolar , Ácido N-Acetilneuramínico do Monofosfato de Citidina/metabolismo , Citoplasma/metabolismo , Deficiências do Desenvolvimento/enzimologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/urina , Retroalimentação , Feminino , Fibroblastos , França , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/fisiopatologia , Erros Inatos do Metabolismo/urina , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Linhagem , Ácidos Siálicos/análise , Uridina Difosfato N-Acetilglicosamina/metabolismoRESUMO
A 15-year-old boy was under anti-epileptic medication (diphenylhydantoine, phenobarbital and Na valproate) for more than five years. He was admitted in cerebral coma and died after 24 hours. The histological findings suggest a valproate induced liver toxicity. This long interval between start of treatment and a possibly related hepatic failure has not been described.
