#269921
ICD+
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| SIALURIA | |||||||||||||||||||||||||||||||||||||||||||||
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| SIALURIA, FRENCH TYPE | |||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that sialuria is caused by mutation in the gene encoding uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase; 603824). Sialuria differs from the sialidoses (256550) in the accumulation and excretion of free sialic acid and normal (or increased) levels of neuraminidase activity. In the disorder originally described by Montreuil et al. (1968) and Fontaine et al. (1968) and characterized by massive excretion of free sialic acid, Kamerling et al. (1979) implicated defective feedback inhibition of one of the enzymes involved in sialic acid synthesis. Seppala et al. (1989) indicated that only 3 bona fide cases appeared to have been discovered: the French case of Montreuil et al. (1968), the Australian case of Wilcken et al. (1987), and an American case studied by his coauthor Barsh. Seppala et al. (1989) studied the patient reported by Wilcken et al. (1987) and a 3-year-old boy who presented at 3 months of age with hepatosplenomegaly, coarse facies, and massive urinary excretion of free N-acetylneuraminic acid (NANA or NeuAc). Both patients had near normal growth and development, unlike patients with lysosomal storage of NANA. In sialuria fibroblasts, 88% of accumulated NANA was in the cytosolic fraction. From a study of cultured fibroblasts, Seppala et al. (1989) derived evidence that the metabolic defect consists of a loss in sensitivity of the rate-limiting enzyme in NANA synthesis, uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase; 603824), to feedback regulation by cytidine monophosphate (CMP)-NANA, as suggested by Thomas et al. (1985). This may be the first instance of a human disease due to defective allosteric inhibition, with apparent preservation of the mutant enzyme's active site. Thomas et al. (1989) demonstrated striking cellular differences between the original French sialuria patient and patients in whom the diagnosis is usually made in the newborn period and whose disorder has been referred to as infantile sialic acid storage disease (ISSD; 269920), caused by mutations in the SLC17A5 gene (604322). While phase microscopy and immunochemical studies showed abnormal storage within intracellular inclusions in ISSD cells, Thomas et al. (1989) found no morphologic evidence of storage within any subcellular organelle in the French sialuria cells. Moreover, comparative subcellular fractionation studies on gradients of colloidal silica showed the excess sialic acid in ISSD cells to be located within the light (buoyant) lysosomal fraction, while the excessive, free sialic acid in the sialuria cells was found in the cytoplasmic fraction with no increased storage within the lysosomal fractions. ISSD is now known to be a lysosomal storage disease due to a defect in the carrier for acidic monosaccharides across lysosomal membranes. It is allelic to Salla disease (604369). In fibroblasts cultured from the 3 known cases of sialuria, Seppala et al. (1991) found 70- to 200-fold increases in soluble sialic acid but normal concentrations of bound sialic acid. They found also that the total cellular content of soluble sialic acid was lowered 14 to 46% by cytidine feeding. They repeated their conclusion that the basic biochemical defect is a failure of CMP-N-acetylneuraminic acid to feedback-inhibit UDP-GlcNAc 2-epimerase. They commented that the inheritance of sialuria has not been determined; however, cells from both parents of 1 sialuria patient contained normal concentrations of free sialic acid, and the parental epimerase activity also responded normally to CMP-NeuAc. To elucidate the molecular mechanism for defective allosteric regulation of UDP-GlcNAc 2-epimerase in sialuria, Seppala et al. (1999) cloned and sequenced the human cDNA encoding the epimerase and determined the mutations in 3 sialuria patients. They identified 3 heterozygous mutations, arg266 to trp (603824.0001), arg266 to gln (603824.0002), and arg263 to leu (603824.0003), which indicated that the allosteric site of the epimerase resides in the region of codons 263 to 266. The heterozygous nature of the mutant allele in all 3 patients demonstrated dominant inheritance of sialuria, i.e., heterozygosity for a mutation in the allosteric site is sufficient to cause the disorder. One of the 3 patients, A.W., had been described by Wilcken et al. (1987). The 2-year-old girl had moderate developmental delay, hepatosplenomegaly, slightly coarse facial features, a large tongue, macrocephaly, and massive urinary excretion of free sialic acid. At age 7 years, she had mild intellectual impairment, with fine-motor difficulty, but attended regular school (Don and Wilcken, 1991). Her growth was at the 10th percentile, and the organomegaly persisted. The other 2 patients were those reported by Weiss et al. (1989) and Gahl et al., 1996 and by Krasnewich et al., 1993. Leroy et al. (2001) reported a sixth case of sialuria. The patient was heterozygous for a G-to-A substitution at nucleotide 848 of the epimerase gene, which resulted in an arg266-to-gln (R266Q; 603824.0004) change. The proband's other allele, as expected, had no mutation. However, the heterozygous R266Q mutation was detected in the patient's mother, who had similarly increased levels of free N-acetylneuraminic acid, thereby confirming the dominant mode of inheritance of this inborn error. Biochemical diagnosis of the proband was verified by the greatly increased levels of free N-acetylneuraminic acid in his cultured fibroblasts, the distribution of NeuAc mainly, (59%) in the cytoplasm, and by the complete failure of CMP-NeuAc to inhibit 2-epimerase activity in the mutant cells. The findings in this family 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. Enns et al. (2001) reported a longitudinal study of 1 of the original sialuria patients to age 11 years. Although he had coarse features and massive hepatomegaly, he showed normal growth and relatively normal development. Pulmonary function testing showed minimal small airway obstruction. At 11 years, he developed intermittent abdominal pain and transient transaminase elevation above his baseline. Enns et al. (2001) suggested that sialuria should be considered in the differential diagnosis of a patient with a phenotype suggestive of mucopolysaccharidosis or oligosaccharidosis in the absence of developmental regression or prominent dysostosis multiplex. | |||||||||||||||||||||||||||||||||||||||||||||
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