MAN1B1-CDG: Three new individuals and associated biochemical profiles

https://doi.org/10.1016/j.ymgmr.2021.100775Get rights and content
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Abstract

Congenital disorders of glycosylation (CDG) constitute an ever-growing group of genetic diseases affecting the glycosylation of proteins. CDG individuals usually present with severe multisystem disorders. MAN1B1-CDG is a CDG with nonspecific clinical symptoms such as intellectual deficiency and developmental delay. Although up to 40 affected individuals were described so far, its final diagnosis is not straightforward using common biochemical methods due to the trace-level accumulation of defective glycan structures. In this study, we present three unreported MAN1B1-CDG individuals and propose a decision tree to reach diagnosis using a panel of techniques ranging from exome sequencing to gel electrophoresis and mass spectrometry. The occurrence of MAN1B1-CDG in patients showing unexplained intellectual disability and development delay, as well as a particular transferrin glycosylation profile, can be ascertained notably using matrix assisted laser desorption/ionization – time of flight (MALDI-TOF) mass spectrometry analysis of endo-β-acetylglucosaminidase H-released serum N-glycans. In addition to reporting new pathogenic variants and additional clinical signs such as hypersialorrhea, we highlight particular biochemical features of MAN1B1-CDG with potential glycoprotein-specific glycosylation defects.

Keywords

CDG
Hypersialorrhea
Intellectual disability
MAN1B1
N-glycan mass spectrometry

Abbreviations

2-DE
two-dimensional electrophoresis
A1AT
α1-antitrypsin
ApoC-III
apolipoprotein C-III
BMI
body mass index
CDG
congenital disorder(s) of glycosylation
CE
capillary electrophoresis
DD
developmental delay
DWI
Diffusion-weighted imaging
Endo H
endo-ß-N-acetylglucosaminidase H
ER
endoplasmic reticulum
ESI-QTOF
electrospray ionization – quadrupole time of flight
FLAIR
fluid-attenuated inversion recovery
HPLC
high performance liquid chromatography
Hpt
haptoglobin
ID
intellectual disability
M6
Man6GlcNAc2
M8A/B/C
Man8GlcNAc2 lacking the first/middle/third terminal mannose
M9
Man9GlcNAc2
MALDI-TOF
matrix assisted laser desorption/ionization – time of flight
Man
mannose
MRI
magnetic resonance imaging
MS
mass spectrometry
PNGase F
peptide-N-glycosidase F
Trf
transferrin
WES
whole exome sequencing

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