{"id":16326,"date":"2020-11-01T11:00:08","date_gmt":"2020-11-01T10:00:08","guid":{"rendered":"https:\/\/genomik-tuebingen.de\/?p=16326"},"modified":"2025-03-10T08:53:21","modified_gmt":"2025-03-10T07:53:21","slug":"n-glycome-analysis-detects-dysglycosylation-missed-by-conventional-methods-in-slc39a8-deficiency","status":"publish","type":"post","link":"https:\/\/cegat.com\/de\/n-glycome-analysis-detects-dysglycosylation-missed-by-conventional-methods-in-slc39a8-deficiency\/","title":{"rendered":"N-glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency."},"content":{"rendered":"

Park JH1 2<\/sup>, Mealer RG3 4 5<\/sup>, Elias AF6 7<\/sup>, Hoffmann S8<\/sup>, Gr\u00fcneberg M2<\/sup>, Biskup S9<\/sup>, Fobker M10<\/sup>, Haven J6<\/sup>, Mangels U2<\/sup>, Reunert J2<\/sup>, Rust S2<\/sup>, Schoof J6<\/sup>, Schwanke C6<\/sup>, Smoller JW3 4<\/sup>, Cummings RD5<\/sup>, Marquardt T2<\/sup><\/p>\n<\/div><\/div><\/div><\/div><\/div>

Abstract<\/h2><\/div><\/div><\/div>

Congenital disorders of glycosylation (CDG) are a growing group of inborn metabolic disorders with multiorgan presentation. SLC39A8-CDG is a severe subtype caused by biallelic mutations in the manganese transporter SLC39A8, reducing levels of this essential cofactor for many enzymes including glycosyltransferases. The current diagnostic standard for disorders of N-glycosylation is the analysis of serum transferrin. Exome and Sanger sequencing were performed in two patients with severe neurodevelopmental phenotypes suggestive of CDG. Transferrin glycosylation was analyzed by high-performance liquid chromatography (HPLC) and isoelectric focusing in addition to comprehensive N-glycome analysis using matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry (MS). Atomic absorption spectroscopy was used to quantify whole blood manganese levels. Both patients presented with a severe, multisystem disorder, and a complex neurological phenotype. Magnetic resonance imaging (MRI) revealed a Leigh-like syndrome with bilateral T2 hyperintensities of the basal ganglia. In patient 1, exome sequencing identified the previously undescribed homozygous variant c.608T>C [p.F203S] in SLC39A8. Patient 2 was found to be homozygous for c.112G>C [p.G38R]. Both individuals showed a reduction of whole blood manganese, though transferrin glycosylation was normal. N-glycome using MALDI-TOF MS identified an increase of the asialo-agalactosylated precursor N-glycan A2G1S1 and a decrease in bisected structures. In addition, analysis of heterozygous CDG-allele carriers identified similar but less severe glycosylation changes. Despite its reliance as a clinical gold standard, analysis of transferrin glycosylation cannot be categorically used to rule out SLC39A8-CDG. These results emphasize that SLC39A8-CDG presents as a spectrum of dysregulated glycosylation, and MS is an important tool for identifying deficiencies not detected by conventional methods.<\/p>\n<\/div><\/div><\/div><\/div><\/div>