The Identification of Sialuria with Different Degrees of Intellectual Disabilities in Children and Adolescents
Adolescent Mental Health
Background: Single nucleotide polymorphism/mutation in the R263L region of the allosteric site of the GNE gene produces a phenotype with an overproduction of intracellular levels of sialic acid and causes sialuria. In sialuria, a defective GNE gene, synthesized with lost feedback inhibition mechanism, produces many developmental delays and varying degrees of intellectual disabilities in children and adolescents. Several mutations in the epimerase and kinase domains exist that cause difficulty in getting a precise and exact effect of the GNE gene on the disease severity and sialic acid levels. This is the first study investigating the molecular basis of neuronal disorders exhibiting sialuria in Pakistani children/ adolescents.
Methodology: The current study quantified the mRNA expression of the GNE gene and urinary sialic acid concentration by Realtime-qRT-PCR and Fluorimetric assays, respectively. The correlation between relative mRNA and urinary sialic acid levels was evaluated by using Pearson Bivariate correlations.
Results: The data show that severely intellectually disabled (I.D.) patients showed significantly reduced mRNA expression levels of the GNE gene compared to controls. The concentrations of free sialic acid in urine were significantly reduced in severe I.D. patients compared to controls. Whereas patients with mild I.D. showed a two-fold increase in sialic acid levels when compared to controls. A significant correlation was found between an increased GNE mRNA and low urinary sialic acid levels from severe I.D. patients.
Conclusion: The effect of the GNE gene is beyond hyposialylation that could hinder N-glycan structure and sialic acid biosynthesis. The study highlighted the possible involvement of sialic acid levels with different degrees of intellectual disabilities in Pakistani children and adolescents.
2. Wen XY, Tarailo-Graovac M, Brand-Arzamendi K, Willems A, Rakic B, Huijben K, Da Silva A, Pan X, El-Rass S, Ng R, Selby K. Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function. JCI insight. 2018;3(24).
3. Bonfanti L. PSA-NCAM in mammalian structural plasticity and neurogenesis. Progress in neurobiology. 2006;80(3):129-164.
4. Rutishauser U. Polysialic acid in the plasticity of the developing and adult vertebrate nervous system. Nat Rev Neurosci. 2008;9(1):26-35.
5. Ishtiaq H, Siddiqui S, Nawaz R, Jamali KS, Khan AG. Sialuria-Related Intellectual Disability in Children and Adolescent of Pakistan: Tenth Patient Described has a Novel Mutation in the GNE Gene. CNS Neurolog Dis Drug Targets. 2020;19(2):127-41.
6. Fontaine G, Biserte G, Montreuil J, Dupont A, Farriaux JP. La sialurie: Un trouble métabolique original? Helv Paediatr Acta Suppl. 1968;17:1-32.
7. Wilcken B, Don N, Greenaway R, Hammond J, Sosula L. Sialuria: a second case. J Inherit Metab Dis. 1987;10(2):97-102.
8. Seppala R, Lehto VP, Gahl WA. 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. 1999;64(6):1563-1569.
9. Krasnewich DM, Tietze FR, Krause WI, Pretzlaff R, Wenger DA, Diwadkar V, Gahl WA. Clinical and biochemical studies in an American child with sialuria. J Biochem Med Metab Biol. 1993;49(1):90-96.
10. Ferreira H, Seppala R, Pinto R, Huizing M, Martins E, Braga AC, Gomes L, Krasnewich DM, Miranda MC, Gahl WA. Sialuria in a Portuguese girl: clinical, biochemical, and molecular characteristics. Mol Genet Metab. 1999;67(2):131-137.