Abstract
BackgroundPrimary or secondary abnormalities of glycosylation have been reported in various brain diseases. Decreased asialotransferrin to sialotransferrin ratio in cerebrospinal fluid (CSF) is a diagnostic marker of leukodystrophies related to mutations of genes encoding translation initiation factor, EIF2B. We investigated the CSF glycome of eIF2B-mutated patients and age-matched normal individuals in order to further characterize the glycosylation defect for possible use as a biomarker.Methodology/Principal FindingsWe conducted a differential N-glycan analysis using MALDI-TOF/MS of permethylated N-glycans in CSF and plasma of controls and eIF2B-mutated patients. We found in control CSF that tri-antennary/bisecting and high mannose structures were highly represented in samples obtained between 1 to 5 years of age, whereas fucosylated, sialylated structures were predominant at later age. In CSF, but not in plasma, of eIF2B-mutated patient samples, we found increased relative intensity of bi-antennary structures and decreased tri-antennary/bisecting structures in N-glycan profiles. Four of these structures appeared to be biomarker candidates of glycomic profiles of eIF2B-related disorders.ConclusionOur results suggest a dynamic development of normal CSF N-glycan profiles from high mannose type structures to complex sialylated structures that could be correlated with postnatal brain maturation. CSF N-glycome analysis shows relevant quantitative changes associated with eIF2B related disorders. This approach could be applied to other neurological disorders involving developmental gliogenesis/synaptogenesis abnormalities.
Highlights
Genetic defects of N-glycan metabolisms due to abnormal hydrolysis, transport or storage and synthesis as in congenital disorders of glycosylation (CDG) are responsible for severe alterations of the CNS including myelination impairment [1]
Our results suggest a dynamic development of normal cerebrospinal fluid (CSF) N-glycan profiles from high mannose type structures to complex sialylated structures that could be correlated with postnatal brain maturation
Decreased CSF asialotransferrin to sialotransferrin ratio is considered as a biomarker of the CACH/VWM disorder [5,6] and can be measured using a HPLC method when 1.5 mL CSF is available [7]
Summary
Genetic defects of N-glycan metabolisms due to abnormal hydrolysis (oligo saccharidosis), transport or storage (sialidosis and sialic acid storage disorders such as Salla disease and infantile sialic acid storage disease) and synthesis as in congenital disorders of glycosylation (CDG) are responsible for severe alterations of the CNS including myelination impairment [1]. Decreased CSF asialotransferrin to sialotransferrin ratio is considered as a biomarker of the CACH/VWM disorder (childhood ataxia with central nervous system hypomyelination/vanishing white matter) [5,6] and can be measured using a HPLC method when 1.5 mL CSF is available [7]. This vacuolating form of leukodystrophy is related to mutations in the initiation factor, eIF2B, an ubiquitous factor involved in the global protein synthesis and its regulation under normal and stress conditions [8,9,10,11,12]. We investigated the CSF glycome of eIF2B-mutated patients and age-matched normal individuals in order to further characterize the glycosylation defect for possible use as a biomarker
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