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Advances in Carbohydrate Chemistry and... 2018Sialic acids are cytoprotectors, mainly localized on the surface of cell membranes with multiple and outstanding cell biological functions. The history of their... (Review)
Review
Sialic acids are cytoprotectors, mainly localized on the surface of cell membranes with multiple and outstanding cell biological functions. The history of their structural analysis, occurrence, and functions is fascinating and described in this review. Reports from different researchers on apparently similar substances from a variety of biological materials led to the identification of a 9-carbon monosaccharide, which in 1957 was designated "sialic acid." The most frequently occurring member of the sialic acid family is N-acetylneuraminic acid, followed by N-glycolylneuraminic acid and O-acetylated derivatives, and up to now over about 80 neuraminic acid derivatives have been described. They appeared first in the animal kingdom, ranging from echinoderms up to higher animals, in many microorganisms, and are also expressed in insects, but are absent in higher plants. Sialic acids are masks and ligands and play as such dual roles in biology. Their involvement in immunology and tumor biology, as well as in hereditary diseases, cannot be underestimated. N-Glycolylneuraminic acid is very special, as this sugar cannot be expressed by humans, but is a xenoantigen with pathogenetic potential. Sialidases (neuraminidases), which liberate sialic acids from cellular compounds, had been known from very early on from studies with influenza viruses. Sialyltransferases, which are responsible for the sialylation of glycans and elongation of polysialic acids, are studied because of their significance in development and, for instance, in cancer. As more information about the functions in health and disease is acquired, the use of sialic acids in the treatment of diseases is also envisaged.
Topics: Animals; Carbohydrate Conformation; Humans; Lysosomal Storage Diseases; Mucolipidoses; N-Acetylneuraminic Acid; Neoplasms; Sialic Acid Storage Disease
PubMed: 30509400
DOI: 10.1016/bs.accb.2018.09.001 -
JIMD Reports 2019Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid...
Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid due to failure of feedback inhibition of the rate-limiting enzyme in the sialic acid synthesis pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). To date, eight cases had been published worldwide, all with heterozygous missense variants at the allosteric site, specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE. The described cases so far have rather homogeneous clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice. The apparent rarity of this disorder is hypothesized to be due to the variable and sometimes transient nature of the clinical features and to the absence of routine testing for urinary sialic acids. Here we present the ninth case of sialuria diagnosed in a child investigated because of clinical signs and symptoms and furthermore describe a novel pathogenic variant in the associated gene, GNE.
PubMed: 29923088
DOI: 10.1007/8904_2018_117 -
CNS & Neurological Disorders Drug... 2020Sialuria is a rare inborn error of metabolism caused by excessive synthesis of sialic acid due to the mutation in the binding site of the cytidine monophosphate-sialic...
BACKGROUND
Sialuria is a rare inborn error of metabolism caused by excessive synthesis of sialic acid due to the mutation in the binding site of the cytidine monophosphate-sialic acid of UDPGlcNAc 2-Epimerase/ManNAc Kinase (GNE/MNK).
OBJECTIVE
This is the first study investigating the molecular basis of neuronal disorders exhibiting sialuria in Pakistani children/adolescents.
METHODS
The current study genotyped GNE SNPs rs121908621, rs121908622 and rs121908623 by using PCR, RFLP, and DNA sequencing methods. Socioeconomic and clinical histories were also recorded.
RESULTS
Our data suggest that clinical symptoms and financial status play a significant role in conferring sialuria related Intellectual Disability (ID). SNP: rs121908623 showed G/A substitution (R263Q) in the GNE gene.
CONCLUSION
We have identified one case study in Pakistan, so this makes our research a leap forward towards the identification of the 10th case study worldwide.
Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Female; Humans; Infant; Intellectual Disability; Male; Mutation; Pakistan; Sialic Acid Storage Disease
PubMed: 32053088
DOI: 10.2174/1871527319666200213115747 -
Evidence for non-lysosomal storage of N-acetylneuraminic acid (sialic acid) in sialuria fibroblasts.Clinical Genetics Oct 1989The results of the investigations reported here indicate that patients affected with the infantile sialic acid storage disorder (ISSD) and the original French sialuria... (Review)
Review
The results of the investigations reported here indicate that patients affected with the infantile sialic acid storage disorder (ISSD) and the original French sialuria patient suffer from distinct and fundamentally different disorders. While phase microscopy and immunochemical studies demonstrated abnormal storage within intracellular inclusions in ISSD cells, no morphological evidence of storage within any subcellular organelles was found in the 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. It is concluded that the sialic acid abnormalities in ISSD and the French type of sialuria are the result of very different biochemical and genetically unrelated abnormalities.
Topics: Fibroblasts; Humans; Inclusion Bodies; Microscopy, Phase-Contrast; Organelles; Sialic Acids
PubMed: 2553307
DOI: 10.1111/j.1399-0004.1989.tb03197.x -
Molecular Genetics and Metabolism Jun 2016Sialuria, a rare inborn error of metabolism, was diagnosed in a healthy 12-year-old boy through whole exome sequencing. The patient had experienced mild delays of speech...
UNLABELLED
Sialuria, a rare inborn error of metabolism, was diagnosed in a healthy 12-year-old boy through whole exome sequencing. The patient had experienced mild delays of speech and motor development, as well as persistent hepatomegaly. Identification of the 8th individual with this disorder, prompted follow-up of the mother-son pair of patients diagnosed over 15years ago. Hepatomegaly was confirmed in the now 19-year-old son, but in the 46-year-old mother a clinically silent liver tumor was detected by ultrasound and MRI. The tumor was characterized as an intrahepatic cholangiocarcinoma (IHCC) and DNA analysis of both tumor and normal liver tissue confirmed the original GNE mutation. As the maternal grandmother in the latter family died at age 49years of a liver tumor, a retrospective study of the remaining pathology slides was conducted and confirmed it to have been an IHCC as well. The overall observation generated the hypothesis that sialuria may predispose to development of this form of liver cancer. As proof of sialuria in the grandmother could not be obtained, an alternate cause of IHCC cannot be ruled out. In a series of 102 patients with IHCC, not a single instance was found with the allosteric site mutation in the GNE gene. This confirms that sialuria is rare even in a selected group of patients, but does not invalidate the concern that sialuria may be a risk factor for IHCC.
SYNOPSIS
Sialuria is a rare inborn error of metabolism characterized by excessive synthesis and urinary excretion of free sialic acid with only minimal clinical morbidity in early childhood, but may be a risk factor for intrahepatic cholangiocarcinoma in adulthood.
Topics: Bile Duct Neoplasms; Child; Cholangiocarcinoma; Female; Hepatomegaly; Heterozygote; Humans; Liver; Liver Neoplasms; Male; Middle Aged; N-Acetylneuraminic Acid; Rare Diseases; Retrospective Studies; Risk Factors; Sialic Acid Storage Disease; Exome Sequencing; Young Adult
PubMed: 27142465
DOI: 10.1016/j.ymgme.2016.04.004 -
Journal of Inherited Metabolic Disease 1987A case of sialuria is described in a girl who presented in the neonatal period with hepatosplenomegaly, and who has moderate developmental delay at the age of 2 years.... (Comparative Study)
Comparative Study
A case of sialuria is described in a girl who presented in the neonatal period with hepatosplenomegaly, and who has moderate developmental delay at the age of 2 years. There was massive urinary excretion of free sialic acid (N-acetylneuraminic acid). The clinical, biochemical and ultramicroscopical features were distinct from those described in Salla disease and in infantile sialic acid storage disorder.
Topics: Child, Preschool; Developmental Disabilities; Diagnosis, Differential; Female; Humans; Liver; Metabolism, Inborn Errors; N-Acetylneuraminic Acid; Sialic Acids
PubMed: 2443758
DOI: 10.1007/BF01800030 -
Journal of Inherited Metabolic Disease 1991
Topics: Carbohydrate Epimerases; Carbohydrate Metabolism, Inborn Errors; Feedback; Female; Follow-Up Studies; Humans; Infant, Newborn; N-Acetylneuraminic Acid; Sialic Acids
PubMed: 1779656
DOI: 10.1007/BF01800480 -
Annual Review of Biochemistry Jun 2019Glycosphingolipids are cell-type-specific components of the outer leaflet of mammalian plasma membranes. Gangliosides, sialic acid-containing glycosphingolipids, are... (Review)
Review
Glycosphingolipids are cell-type-specific components of the outer leaflet of mammalian plasma membranes. Gangliosides, sialic acid-containing glycosphingolipids, are especially enriched on neuronal surfaces. As amphi-philic molecules, they comprise a hydrophilic oligosaccharide chain attached to a hydrophobic membrane anchor, ceramide. Whereas glycosphingolipid formation is catalyzed by membrane-bound enzymes along the secretory pathway, degradation takes place at the surface of intralysosomal vesicles of late endosomes and lysosomes catalyzed in a stepwise fashion by soluble hydrolases and assisted by small lipid-binding glycoproteins. Inherited defects of lysosomal hydrolases or lipid-binding proteins cause the accumulation of undegradable material in lysosomal storage diseases (GM1 and GM2 gangliosidosis; Fabry, Gaucher, and Krabbe diseases; and metachromatic leukodystrophy). The catabolic processes are strongly modified by the lipid composition of the substrate-carrying membranes, and the pathological accumulation of primary storage compounds can trigger an accumulation of secondary storage compounds (e.g., small glycosphingolipids and cholesterol in Niemann-Pick disease).
Topics: Animals; Glycosphingolipids; Humans; Lysosomal Storage Diseases; Lysosomes
PubMed: 31220974
DOI: 10.1146/annurev-biochem-013118-111518 -
Chembiochem : a European Journal of... Jul 2017Sialuria is a rare autosomal dominant disorder of mammalian metabolism, caused by defective feedback inhibition of the UDP-N-acetylglucosamine-2-epimerase...
Sialuria is a rare autosomal dominant disorder of mammalian metabolism, caused by defective feedback inhibition of the UDP-N-acetylglucosamine-2-epimerase N-acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis. Sialuria is characterized by overproduction of free sialic acid in the cell cytoplasm. Patients exhibit vastly increased urinary excretion of sialic acid and show differently pronounced developmental delays. The physiopathology of sialuria is not well understood. Here we established a transgenic mouse line that expresses GNE containing the sialuria mutation R263L, in order to investigate the influence of an altered sialic acid concentration on the organism. The transgenic mice that expressed the mutated RNA excreted up to 400 times more N-acetylneuraminic acid than wild-type mice. Additionally, we found higher sialic acid concentration in the brain cytoplasm. Analyzing the (poly)sialylation of neural cell adhesion molecule (NCAM) revealed increased polysialylation in brains of transgenic mice compared to wild-type. However, we found only minor changes in membrane-bound sialylation in various organs but, surprisingly, a significant increase in surface sialylation on leukocytes. Our results suggest that the intracellular sialic acid concentration regulates polysialylation on NCAM in vivo; this could play a role in the manifestation of the developmental delays in sialuria patients.
Topics: Age Factors; Animals; Brain; Disease Models, Animal; Feedback, Physiological; Humans; Leukocytes; Liver; Mice; Mice, Transgenic; Multienzyme Complexes; Mutation; N-Acetylneuraminic Acid; Neural Cell Adhesion Molecules; Organ Specificity; Protein Processing, Post-Translational; Sialic Acid Storage Disease
PubMed: 27966821
DOI: 10.1002/cbic.201600580