Alternative titles; symbols
SNOMEDCT: 238051008, 34566007; ORPHA: 3166; DO: 3659;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9p13.3 | Sialuria | 269921 | Autosomal dominant | 3 | GNE | 603824 |
A number sign (#) is used with this entry because of evidence that sialuria is caused by heterozygous mutation in the gene encoding uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase; 603824) on chromosome 9p13.
Sialuria is a rare inborn error of metabolism in which excessive free sialic acid is synthesized. Clinical features include hepatosplenomegaly, coarse facial features, and varying degrees of developmental delay (summary by Enns et al., 2001).
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.
Wilcken et al. (1987) described a 2-year-old girl (A.W.) with 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.
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 with infantile sialic acid storage disease (ISSD; 269920). Whereas 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, whereas the excessive, free sialic acid in the sialuria cells was found in the cytoplasmic fraction with no increased storage within the lysosomal fractions.
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 noted that 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.
Leroy et al. (2001) reported a patient with sialuria who was heterozygous for a mutation in the epimerase gene (R266Q; 603824.0002). The same heterozygous 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 (J.C.) 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 age 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.
Enns et al. (2001) stated that only 5 patients with sialuria had been reported worldwide.
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 other 2 patients were those reported by Weiss et al. (1989) and Gahl et al., 1996 and by Krasnewich et al., 1993.
Don, N. A., Wilcken, B. Sialuria: a follow-up report. J. Inherit. Metab. Dis. 14: 942 only, 1991. [PubMed: 1779656] [Full Text: https://doi.org/10.1007/BF01800480]
Enns, G. M., Seppala, R., Musci, T. J., Weisiger, K., Ferrell, L. D., Wenger, D. A., Gahl, W. A., Packman, S. Clinical course and biochemistry of sialuria. J. Inherit. Metab. Dis. 24: 328-336, 2001. [PubMed: 11486897] [Full Text: https://doi.org/10.1023/a:1010588115479]
Fontaine, G., Biserte, G., Montreuil, A., Dupont, A., Farriaux, J. P. La sialurie: un trouble metabolique original. Helv. Paediat. Acta 23 (suppl. XVII): 1-32, 1968. [PubMed: 5688324]
Gahl, W. A., Krasnewich, D. M., Williams, J. C. Sialidoses.:In: Moser, H. W. (ed.) : Handbook of Clinical Neurology. Vol. 22. Amsterdam: Elsevier 1996. Pp. 353-375.
Kamerling, J. P., Strecker, G., Farriaux, J. P., Dorland, L., Haverkamp, J., Vliegenthart, J. F. G. Acetamidoglucal, a new metabolite isolated from the urine of a patient with sialuria. Biochim. Biophys. Acta 583: 403-408, 1979. [PubMed: 444571] [Full Text: https://doi.org/10.1016/0304-4165(79)90465-3]
Krasnewich, D. M., Tietze, F., Krause, W., Pretzlaff, R., Wenger, D. A., Diwadkar, V., Gahl, W. A. Clinical and biochemical studies in an American child with sialuria. Biochem. Med. Metab. Biol. 49: 90-96, 1993. [PubMed: 8439453] [Full Text: https://doi.org/10.1006/bmmb.1993.1010]
Leroy, J. G., Seppala, R., Huizing, M., Dacremont, G., De Simpel, H., Van Coster, R. N., Orvisky, E., Krasnewich, D. M., Gahl, W. A. Dominant inheritance of sialuria, an inborn error of feedback inhibition. Am. J. Hum. Genet. 68: 1419-1427, 2001. [PubMed: 11326336] [Full Text: https://doi.org/10.1086/320598]
Montreuil, J., Biserte, G., Strecker, G., Spik, G., Fontaine, G., Farriaux, J.-P. Description d'un nouveau type du meliturie: la sialurie. Clin. Chim. Acta 21: 61-68, 1968. [PubMed: 5658957] [Full Text: https://doi.org/10.1016/0009-8981(68)90011-9]
Seppala, R., Lehto, V.-P., Gahl, W. A. Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. Am. J. Hum. Genet. 64: 1563-1569, 1999. [PubMed: 10330343] [Full Text: https://doi.org/10.1086/302411]
Seppala, R., Tietze, F., Krasnewich, D., Weiss, P., Ashwell, G., Barsh, G., Thomas, G. H., Packman, S., Gahl, W. A. Sialic acid metabolism in sialuria fibroblasts. J. Biol. Chem. 266: 7456-7461, 1991. [PubMed: 2019577]
Seppala, R., Tietze, F., Weiss, P., Ashwell, G., Barsh, G., Gahl, W. A. The metabolic defect in sialuria: lack of feedback control of uridine diphosphate N-acetylglucosamine 2-epimerase (UDP-GlcNAc epimerase). (Abstract) Am. J. Hum. Genet. 45 (suppl.): A11 only, 1989.
Thomas, G. H., Reynolds, L. W., Miller, C. S. Overproduction of N-acetylneuraminic acid (sialic acid) by sialuria fibroblasts. Pediat. Res. 19: 451-455, 1985. [PubMed: 4000771] [Full Text: https://doi.org/10.1203/00006450-198505000-00009]
Thomas, G. H., Scocca, J., Miller, C. S., Reynolds, L. Evidence for non-lysosomal storage of N-acetylneuraminic acid (sialic acid) in sialuria fibroblasts. Clin. Genet. 36: 242-249, 1989. [PubMed: 2553307] [Full Text: https://doi.org/10.1111/j.1399-0004.1989.tb03197.x]
Weiss, P., Tietze, F., Gahl, W. A., Seppala, R., Ashwell, G. Identification of the metabolic defect in sialuria. J. Biol. Chem. 264: 17635-17636, 1989. [PubMed: 2808337]
Wilcken, B., Don, N., Greenaway, R., Hammond, J., Sosula, L. Sialuria: a second case. J. Inherit. Metab. Dis. 10: 97-102, 1987. [PubMed: 2443758] [Full Text: https://doi.org/10.1007/BF01800030]