Park JH1 2, Mealer RG3 4 5, Elias AF6 7, Hoffmann S8, Grüneberg M2, Biskup S9, Fobker M10, Haven J6, Mangels U2, Reunert J2, Rust S2, Schoof J6, Schwanke C6, Smoller JW3 4, Cummings RD5, Marquardt T2
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.
- Department of Clinical Sciences, Neurosciences, Umeå University, Umeå, Sweden.
- Department of General Pediatrics, University of Münster, Münster, Germany.
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
- The Stanley Center for Psychiatric Research at Broad Institute of Harvard/MIT, Cambridge, Massachusetts, USA.
- National Center for Functional Glycomics, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
- Department of Medical Genetics, Shodair Children’s Hospital, Helena, Montana, USA.
- Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
- Zentrum für Sozial- und Neuropädiatrie, Vivantes Klinikum Neukölln, Berlin, Germany.
- CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany.
- Center for Laboratory Medicine, University Hospital Münster, Münster, Germany.