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Scientific result | Mass spectrometry | Biomarkers | Genetic diseases

Biochemical analysis and mass spectrometry for the diagnosis of congenital disorders of glycosylation

​A collaboration initiated in 2017 between AP-HP (Bichat Hospital), Paris-Saclay University (Inserm 1193) and the Laboratoire d'Études du Métabolisme des Médicaments (LEMM/SPI/DMTS), leading to 4 publications in 2021, is advancing knowledge on the origin of certain congenital disorders of glycosylation, through the identification of specific biochemical biomarkers.

Published on 4 January 2022

​Glycosylation is the addition, in several successive steps, of monosaccharides (sugars), usually to a protein. It is a complex cellular process, universal in eukaryotic organisms and highly conserved during evolution. It is estimated that about 1-2% of the human genome codes for enzymes involved in glycoprotein assembly. Mutation of one of the genes encoding these enzymes can significantly disrupt this cellular machinery and result in rare, usually autosomal recessive, diseases called Congenital Disorders of Glycosylation (CDG). These diseases, whose etiology is often complex, are responsible for multiple disorders, leading to very heterogeneous and unspecific clinical symptoms (neurological disorders, skin abnormalities, coagulation disorders, cytolysis and hepatic fibrosis, etc.). Today, their diagnosis is mainly based on the detection of glycosylation abnormalities of serum glycoproteins, which allow to establish the causality of mutations identified by different genetic sequencing techniques.

Thanks to a panel of advanced methodologies, ranging from electrophoresis to mass spectrometry, LEMM and AP-HP researchers were able to identify protein glycosylation defects in serum samples from several patients with multisystem disorders such as : i) liver dysfunction, pro- and anticoagulant factor deficiency and cardiac problems (publications 1 and 4); ii) intellectual disability and developmental delay (publications 2 and 3). Most of these CDG were associated with a disruption of the homeostasis of the Golgi apparatus (pH, vesicular trafficking), the main intracellular organelle for glycosylation pathways. Biochemical analyses performed at the LEMM by mass spectrometry and at the Bichat Hospital by several electrophoretic techniques revealed "glycomic" profiles allowing to formally establish the causality of mutations discovered after Whole Exome Sequencing (WES) of patients. For MAN1B1-CDG (publication 2), the very rare COG4-CDG (publication 3) and the dominantly inherited SLC37A4-CDG (publications 1 and 4), apparently specific blood biomarkers with high diagnostic potential have been identified. From a more fundamental point of view, the identification of these biomarkers has also made it possible to advance our understanding of the pathogenesis of some of these diseases.

Scheme of the experimental protocol for the mass spectrometric analysis of N-glycans in serum samples © LEMM/SPI/CEA

The discovery of new blood biomarkers is a significant advance in the diagnosis of CDG and in the fine understanding of the affected glycosylation pathways. Thanks to the glycomic and metabolomic approaches currently developed at the LEMM, new CDG are being characterized, with very encouraging prospects, not only in terms of diagnosis, but also in terms of treatment.

Exome: part of the genome of a eukaryotic organism consisting of the exons, i.e. the portions of the genes that are expressed to synthesize the functional products in the form of proteins.


François Fenaille (head of LEMM/SPI/DMTS, responsible for the mass spectrometry platform)

Arnaud Bruneel (AP-HP, Metabolic and Cellular Biochemistry, Hôpital Bichat-Claude Bernard)

Link to the website of the CDG-Bichat study group:

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