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Review
. 2018 Apr 27;19(5):1304.
doi: 10.3390/ijms19051304.

CDG Therapies: From Bench to Bedside

Sandra Brasil  1   2 , Carlota Pascoal  3   4   5 , Rita Francisco  6   7   8 , Dorinda Marques-da-Silva  9   10   11 , Giuseppina Andreotti  12 , Paula A Videira  13   14   15 , Eva Morava  16   17 , Jaak Jaeken  18   19 , Vanessa Dos Reis Ferreira  20   21
Affiliations
Review

CDG Therapies: From Bench to Bedside

Sandra Brasil et al. Int J Mol Sci. .

Abstract

Congenital disorders of glycosylation (CDG) are a group of genetic disorders that affect protein and lipid glycosylation and glycosylphosphatidylinositol synthesis. More than 100 different disorders have been reported and the number is rapidly increasing. Since glycosylation is an essential post-translational process, patients present a large range of symptoms and variable phenotypes, from very mild to extremely severe. Only for few CDG, potentially curative therapies are being used, including dietary supplementation (e.g., galactose for PGM1-CDG, fucose for SLC35C1-CDG, Mn2+ for TMEM165-CDG or mannose for MPI-CDG) and organ transplantation (e.g., liver for MPI-CDG and heart for DOLK-CDG). However, for the majority of patients, only symptomatic and preventive treatments are in use. This constitutes a burden for patients, care-givers and ultimately the healthcare system. Innovative diagnostic approaches, in vitro and in vivo models and novel biomarkers have been developed that can lead to novel therapeutic avenues aiming to ameliorate the patients’ symptoms and lives. This review summarizes the advances in therapeutic approaches for CDG.

Keywords: animal models; biomarkers; clinical trials; congenital disorders of glycosylation (CDG); diagnosis; dietary supplementation; galactose; mannose; pharmacological chaperones; therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Dietary supplementation approaches under investigation for ALG1-CDG, MPI-CDG, PMM2-CDG and MAGT1-CDG. For MPI-CDG and PMM-CDG, exogenous Man or Man-1-P respectively, is administered (blue arrows). For PMM2-CDG, glucose starvation (blue arrow) was also studied. For ALG1-CDG, Man-1-P supplementation (black arrow) might also represent a promising approach. Mg2+ supplementation (blue arrow) is used to correct MAGT1 transporter defect (dotted yellow line). These therapeutic approaches aim to recover the metabolic pathways (black arrows) and ultimately, the normal glycosylation profile (bold black arrow).
Figure 2
Figure 2
Dietary supplementation approaches under investigation for CAD-CDG, GNE-CDG, NANS-CDG and SLC35A2-CDG. Uridine supplementation has been tried for CAD-CDG (green arrow). Combined administration of uridine and Gal aims to increase Gal-UPD levels (yellow, green, black and light blue arrows). This allows the bypass of SLC35A2 transporter defect. ManNAc supplementation (dark blue arrow) has been used for GNE-CDG and NANS-CDG. These therapeutic approaches aim to recover the metabolic pathways (black arrows) and ultimately, the normal glycosylation profile (bold black arrow).
Figure 3
Figure 3
Dietary supplementation approaches under investigation for PGM1-CDG and PGM3-CDG. GlcNAc supplementation has been tried in vitro for PGM3-CDG (blue arrow) while for PGM1-CDG, Glc, uridine and Gal (blue arrows) have been tried. These therapeutic approaches aim to recover the metabolic pathways (black arrows) and ultimately, the normal glycosylation profile (bold black arrow).
Figure 4
Figure 4
Dietary supplementation approaches under investigation for PIGM-CDG and PIGO-CDG. Vitamin B6 due to its ability to increase GABA expression has been tried for PIGO-CDG (blue arrows). Sodium butirate, which can increase PIGM expression, has been tried for PIGM-CDG (blue arrow). These therapeutic approaches aim to recover the metabolic pathways (black arrows) and ultimately, the final end product (bold black arrow).
Figure 5
Figure 5
Dietary supplementation approaches under investigation for TMEM165-CDG and SLC39A8-CDG. Impaired transport of metal ions (dotted yellow lines), can be circumvented by Mn2+ supplementation (yellow and black lines). These therapeutic approaches aim to recover the metabolic pathways (black arrows) and ultimately, the final end product (bold black arrow).
Figure 6
Figure 6
Dietary supplementation approaches under investigation for ISPD-CDG. ISPD synthetizes CDP-ribitol from CDP and D-ribitol-5-P, with the release of PPi (black and blue arrows). Ribitol supplementation (blue arrow) aims to circumvent ribitol shortage and ultimately the recovery of α-DG glycosylation (bold back arrow).
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