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

Christel Tran; Licia Turolla; Diana Ballhausen; Sandrine Cornaz Buros; Tony Teav; Hector Gallart-Ayala; Julijana Ivanisevic; Mohamed Faouzi; Dirk J Lefeber; Ivan Ivanovski; Sara Giangiobbe; Stefano Giuseppe Caraffi; Livia Garavelli; Andrea Superti-Furga

doi:10.1016/j.ymgmr.2021.100777

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

Mol Genet Metab Rep. 2021 Jun 26:28:100777. doi: 10.1016/j.ymgmr.2021.100777. eCollection 2021 Sep.

Authors

Affiliations

¹ Center for Molecular Diseases, Division of Genetic Medicine, University of Lausanne and University Hospital of Lausanne, Switzerland.
² Medical Genetics Unit, Azienda ULSS 2, Treviso, Italy.
³ Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, Switzerland.
⁴ Department of Paediatrics, Neuropediatrics, Bern University Hospital, Switzerland.
⁵ Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Switzerland.
⁶ Division of Biostatistics, Center for Primary Care and Public Health (Unisanté), University of Lausanne, Switzerland.
⁷ Translational Metabolic Laboratory, Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
⁸ Medical Genetics Unit, Maternal and Child Health Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
⁹ Institute of Medical Genetics, University of Zurich, Switzerland.

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.

Keywords: Brain gangliosides; Developmental delay; NANS deficiency; Nutrition therapy; Sialic acid.