Aspartylglycosamine is a biomarker for NGLY1-CDDG, a congenital disorder of deglycosylation.
BACKGROUND
NGLY1-CDDG is a congenital disorder of deglycosylation caused by a defective peptide:N-glycanase (PNG). To date, all but one of the reported patients have been diagnosed through whole-exome or whole-genome sequencing, as no biochemical marker was available to identify this disease in patients. Recently, a potential urinary biomarker was reported, but the data presented suggest that this marker may be excreted intermittently.


METHODS
In this study, we performed untargeted direct-infusion high-resolution mass spectrometry metabolomics in seven dried blood spots (DBS) from four recently diagnosed NGLY1-CDDG patients, to test for small-molecule biomarkers, in order to identify a potential diagnostic marker. Results were compared to 125 DBS of healthy controls and to 238 DBS of patients with other diseases.


RESULTS
We identified aspartylglycosamine as the only significantly increased compound with a median Z-score of 4.8 (range: 3.8-8.5) in DBS of NGLY1-CDDG patients, compared to a median Z-score of -0.1 (range: -2.1-4.0) in DBS of healthy controls and patients with other diseases.


DISCUSSION
The increase of aspartylglycosamine can be explained by lack of function of PNG. PNG catalyzes the cleavage of the proximal N-acetylglucosamine residue of an N-glycan from the asparagine residue of a protein, a step in the degradation of misfolded glycoproteins. PNG deficiency results in a single N-acetylglucosamine residue left attached to the asparagine residue which results in free aspartylglycosamine when the glycoprotein is degraded. Thus, we here identified aspartylglycosamine as the first potential small-molecule biomarker in DBS for NGLY1-CDDG, making a biochemical diagnosis for NGLY1-CDDG potentially feasible.
['Haijes|Hanneke A|HA|', 'de Sain-van der Velden|Monique G M|MGM|', 'Prinsen|Hubertus C M T|HCMT|', 'Willems|Anke P|AP|', 'van der Ham|Maria|M|', 'Gerrits|Johan|J|', 'Couse|Madeline H|MH|', 'Friedman|Jan M|JM|', 'van Karnebeek|Clara D M|CDM|', 'Selby|Kathryn A|KA|', 'van Hasselt|Peter M|PM|', 'Verhoeven-Duif|Nanda M|NM|', 'Jans|Judith J M|JJM|']
D000117:Acetylglucosamine D000293:Adolescent D000328:Adult D015415:Biomarkers D016022:Case-Control Studies D002648:Child D002675:Child, Preschool D018981:Congenital Disorders of Glycosylation D059788:Dried Blood Spot Testing D005260:Female D006801:Humans D007223:Infant D008297:Male D013058:Mass Spectrometry D009154:Mutation D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
Aspartylglycosamine Biomarker NGLY1-CDDG Peptide:N-glycanase