This study is aimed at assessing the impact of short-term (3 days) exogenous sialic acid supplementation on endogenous biomarkers of sialic acid metabolism in NANS deficient patients.

NANS deficiency is a genetic disorder presenting clinically with intellectual development disorder, skeletal dysplasia and dysmorphic features. It has recently been described in 9 patients (4 children and 5 adults). Biallelic mutations in the NANS (N-Acetylneuraminic acid synthase) gene cause a block in the endogenous synthesis of sialic acid and accumulation of the precursor, N-acetyl mannosamine (ManNAc). In a cell culture model, this block results in hyposialylation of glycoproteins and glycolipids. It seems likely that in human, this enzyme deficiency impairs the sialylation of glycolipids and glycoproteins, known to be essential for brain development. Exogenously added sialic acid partially rescued the phenotype of NANS-deficient zebra fish. Currently there is no approved treatment for patients with NANS deficiency. The investigators concluded that exogenous sialic acid supplementation might be useful for NANS patients. Given that sialic acid is found as both, a free sugar and in a bound form in standard nutrition as well as in high quantities in breast milk, it can be considered as a safe nutritional ingredient; this notion is fully supported by animal toxicity studies.

The use of sialic acid in NANS deficiency is in line with oral supplementation of specific sugars for treatment of other glycosylation and sialylation defects such as congenital disorders of glycosylation (CDG) and myopathy with mutation in the gene GNE. This novel monosaccharide therapy represents an opportunity to address fundamental biochemical questions about the relative contribution of endogenous and dietary sources on sialic acid metabolism and its potential role as a future therapy for NANS patients.

Inclusion Criteria for controls:

• 4 healthy adults aged 18 to 60 years (inclusion in Switzerland)

Inclusion Criteria for subjects with NANS deficiency:

• 4 adults aged 18 to 60 years with genetically proven NANS deficiency (inclusion in Italy)
• 2 children aged 1 to 18 years with genetically proven NANS deficiency (inclusion in Switzerland)

Exclusion Criteria for controls:

• Medication, Restrictive diet (e.g. lactose free diet), obesity or other co-morbidities (e.g. neurological disease, developmental delay)

No exclusion Criteria for subjects