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J Inherit Metab Dis ; 43(6): 1370-1381, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32852845

RESUMO

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.


Assuntos
Gânglios da Base/fisiopatologia , Proteínas de Transporte de Cátions/genética , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/fisiopatologia , Adolescente , Proteínas de Transporte de Cátions/deficiência , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Glicosilação , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Manganês/metabolismo , Espectrometria de Massas , Fenótipo , Transferrina/análise , Sequenciamento do Exoma , Adulto Jovem
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