NANS deficiency linked to brain development

Wevers, Ron.bmp

A large, international collaboration including Angel Ashikov, Dirk Lefeber and Ron Wevers (photo up) of the Radboudumc, including the Research Institutes Donders and RIMLS, has succeeded in linking NANS deficiency to brain and skeletal development.

Their research describes a novel inborn error of metabolism causing a combination of intellectual developmental disability, skeletal abnormalities, epilepsy and short stature. Crucially, their discovery can pave the way for potential treatment options for this rare disorder in sialic acid biosynthesis. 

NANS deficiency is a severe disorder that is linked to epilepsy, skeletal abnormalities, and intellectual disabilities. The disorder was only recently diagnosed by this international consortium and is considered extremely rare (see Nolin's story for the insights of an affected family). In order to understand this disorder and develop appropriate medical care for it, more knowledge about it is urgently needed.

NANS deficiency: an elusive disorder

In NANS deficiency, the body is unable to consistently provide sufficient amounts of sialic acid with which a variety of bodily processes are fueled. NANS is also the gene that lends the condition its name; this gene is a key player in the production of sialic acid in the body. Sialic acid is an important constituent of glycans in glycoproteins and glycolipids.   

A large, international collaboration of research including the Research Institutes Donders and RIMLS Angel Ashikov, Dirk Lefeber and Ron Wevers has now discovered the genetics and biochemistry that underlie NANS deficiency. The team used a combination of genomics and metabo­lomics techniques. The Nijmegen team found developed an untargeted metabolomics technique based on LC-Qtof-MS and applied it on body fluids of patients. This novel technique is referred to as Next Generation Metabolic Screening. The patients with the NANS deficiency were found to have very high concentration of N-acetyl-D-mannosa­mine, a precursor of sialic acid. However, the metabolism of these patients appeared to be unable to turn this precursor into sialic acid, a negatively charged sugar that is highly important for many bodily functions in the brain and other tissues. This observation led the way to identifying the NANS-gene that turned out to have pathogenic mutations in the patients. The consortium diagnosed nine patients with this disease, all having a similar clinical phenotype, mutations in NANS and identical biochemical findings. 

The researchers then studied zebrafish embryos whose equivalent of the human NANS gene was knocked out experimentally. These embryos developed several developmental abnormalities that mirror those seen in human patients. Crucially, by adding sialic acid to the fish's embryo water, the development of the affected fish could be partially improved suggesting that NANS-deficiency may well be a treatable inborn error of metabolism.

Understanding NANS and providing care

The study strongly supports the notion that mutations of the NANS gene are indeed responsible for causing the symptoms of NANS deficiency, by hindering the biosynthesis of sialic acid. Given that the human brain in particular requires large amounts of sialic acids, mutations of NANS will have severe consequences for brain development. Importantly, the study also suggest that  supplementing sialic acids might improve the development of patients suffering from NANS. These insights can pave the way for new treatments that improve the development and quality of life of those born with the disorder.

Read the original study at Nature genetics.

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