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      The fate of orally administered sialic acid: First insights from patients with N-acetylneuraminic acid synthase deficiency and control subjects

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          Abstract

          Background

          In NANS deficiency, biallelic mutations in the N-acetylneuraminic acid synthase ( NANS) gene impair the endogenous synthesis of sialic acid ( N-acetylneuraminic acid) leading to accumulation of the precursor, N-acetyl mannosamine (ManNAc), and to a multisystemic disorder with intellectual disability. The aim of this study was to determine whether sialic acid supplementation might be a therapeutic avenue for NANS-deficient patients.

          Methods

          Four adults and two children with NANS deficiency and four adult controls received oral NeuNAc acid (150 mg/kg/d) over three days. Total NeuNAc, free NeuNAc and ManNAc were analyzed in plasma and urine at different time points.

          Results

          Upon NeuNAc administration, plasma free NeuNAc increased within hours ( P < 0.001) in control and in NANS-deficient individuals. Total and free NeuNAc concentrations also increased in the urine as soon as 6 h after beginning of oral administration in both groups. NeuNAc did not affect plasma and urinary ManNAc, that remained higher in NANS deficient subjects than in controls (day 1–3; all P < 0.01). Oral NeuNAc was well tolerated with no significant side effects.

          Discussion

          Orally administered free NeuNAc was rapidly absorbed but also rapidly excreted in the urine. It did not change ManNAc levels in either patients or controls, indicating that it may not achieve enough feedback inhibition to reduce ManNAc accumulation in NANS-deficient subjects. Within the limitations of this study these results do not support a potential for oral free NeuNAc in the treatment of NANS deficiency but they provide a basis for further therapeutic approaches in this condition.

          Highlights

          • •

            NANS deficiency is a recessively inherited disorder.

          • •

            Patients present with cognitive delay, bone dysplasia and dysmorphic features.

          • •

            Endogenous synthesis of sialic acid is blocked with accumulation of the precursor, N-acetyl mannosamine (ManNAc)

          • •

            Sialic acid supplementation in NANS deficiency was ineffective in reducing ManNAc.

          • •

            Nutritional therapy for NANS deficiency requires further exploration.

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          A new equation to estimate glomerular filtration rate.

          Andrew Levey, Lesley Stevens, Christopher H Schmid … (2009)
          Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. 8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES. GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%). The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. National Institute of Diabetes and Digestive and Kidney Diseases.
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            Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration.

            Ronald L Schnaar, Rita Gerardy-Schahn, Herbert Hildebrandt (2014)
            Every cell in nature carries a rich surface coat of glycans, its glycocalyx, which constitutes the cell's interface with its environment. In eukaryotes, the glycocalyx is composed of glycolipids, glycoproteins, and proteoglycans, the compositions of which vary among different tissues and cell types. Many of the linear and branched glycans on cell surface glycoproteins and glycolipids of vertebrates are terminated with sialic acids, nine-carbon sugars with a carboxylic acid, a glycerol side-chain, and an N-acyl group that, along with their display at the outmost end of cell surface glycans, provide for varied molecular interactions. Among their functions, sialic acids regulate cell-cell interactions, modulate the activities of their glycoprotein and glycolipid scaffolds as well as other cell surface molecules, and are receptors for pathogens and toxins. In the brain, two families of sialoglycans are of particular interest: gangliosides and polysialic acid. Gangliosides, sialylated glycosphingolipids, are the most abundant sialoglycans of nerve cells. Mouse genetic studies and human disorders of ganglioside metabolism implicate gangliosides in axon-myelin interactions, axon stability, axon regeneration, and the modulation of nerve cell excitability. Polysialic acid is a unique homopolymer that reaches >90 sialic acid residues attached to select glycoproteins, especially the neural cell adhesion molecule in the brain. Molecular, cellular, and genetic studies implicate polysialic acid in the control of cell-cell and cell-matrix interactions, intermolecular interactions at cell surfaces, and interactions with other molecules in the cellular environment. Polysialic acid is essential for appropriate brain development, and polymorphisms in the human genes responsible for polysialic acid biosynthesis are associated with psychiatric disorders including schizophrenia, autism, and bipolar disorder. Polysialic acid also appears to play a role in adult brain plasticity, including regeneration. Together, vertebrate brain sialoglycans are key regulatory components that contribute to proper development, maintenance, and health of the nervous system.
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              Sialic acid is an essential nutrient for brain development and cognition.

              Bing Wang (2008)
              The rapid growth of infant brains places an exceptionally high demand on the supply of nutrients from the diet, particularly for preterm infants. Sialic acid (Sia) is an essential component of brain gangliosides and the polysialic acid (polySia) chains that modify neural cell adhesion molecules (NCAM). Sia levels are high in human breast milk, predominately as N-acetylneuraminic acid (Neu5Ac). In contrast, infant formulas contain a low level of Sia consisting of both Neu5Ac and N-glycolylneuraminic acid (Neu5Gc). Neu5Gc is implicated in some human inflammatory diseases. Brain gangliosides and polysialylated NCAM play crucial roles in cell-to-cell interactions, neuronal outgrowth, modifying synaptic connectivity, and memory formation. In piglets, a diet rich in Sia increases the level of brain Sia and the expression of two learning-related genes and enhances learning and memory. The purpose of this review is to summarize the evidence showing the importance of dietary Sia as an essential nutrient for brain development and cognition.
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                Author and article information

                Contributors
                Christel Tran
                Journal
                Journal ID (nlm-ta): Mol Genet Metab Rep
                Journal ID (iso-abbrev): Mol Genet Metab Rep
                Title: Molecular Genetics and Metabolism Reports
                Publisher: Elsevier
                ISSN (Electronic): 2214-4269
                Publication date PMC-release: 26 June 2021
                Publication date Collection: September 2021
                Publication date (Electronic): 26 June 2021
                Volume: 28
                Electronic Location Identifier: 100777
                Affiliations
                [a ]Center for Molecular Diseases, Division of Genetic Medicine, University of Lausanne and University Hospital of Lausanne, Switzerland
                [b ]Medical Genetics Unit, Azienda ULSS 2, Treviso, Italy
                [c ]Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, Switzerland
                [d ]Department of Paediatrics, Neuropediatrics, Bern University Hospital, Switzerland
                [e ]Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Switzerland
                [f ]Division of Biostatistics, Center for Primary Care and Public Health (Unisanté), University of Lausanne, Switzerland
                [g ]Translational Metabolic Laboratory, Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands
                [h ]Medical Genetics Unit, Maternal and Child Health Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
                [i ]Institute of Medical Genetics, University of Zurich, Switzerland
                Author notes
                [* ]Corresponding author at: Center for Molecular Diseases, Lausanne University Hospital, Division of Genetic Medicine, Beaumont-02/248, CH-1011, Lausanne 1011, Switzerland. christel.tran@ 123456chuv.ch
                Article
                Publisher Item ID: S2214-4269(21)00071-9 Publisher ID: 100777
                DOI: 10.1016/j.ymgmr.2021.100777
                PMC ID: 8251509
                PubMed ID: 34258226
                SO-VID: b411eb29-159d-44e0-ac84-caa759bbf327
                Copyright © © 2021 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 16 April 2021
                Date revision received : 15 June 2021
                Date accepted : 15 June 2021
                Categories
                Subject: Research Paper

                Keywords: sialic acid,nans deficiency,developmental delay,nutrition therapy,brain gangliosides
                Data availability:
                Keywords: sialic acid, nans deficiency, developmental delay, nutrition therapy, brain gangliosides

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