Nutrition interventions in congenital disorders of glycosylation

Abstract

Congenital disorders of glycosylation (CDG) are a group of more than 160 inborn errors of metabolism affecting multiple pathways of protein and lipid glycosylation. Patients present with a wide range of symptoms and therapies are only available for very few subtypes. Specific nutritional treatment options for certain CDG types include oral supplementation of monosaccharide sugars, manganese, uridine, or pyridoxine. Additional management includes specific diets (i.e., complex carbohydrate or ketogenic diet), iron supplementation, and albumin infusions. We review the dietary management in CDG with a focus on two subgroups: N-linked glycosylation defects and GPI-anchor disorders.

Keywords: GPI-anchor disorder; N-linked CDG; hypoglycemia; manganese; monosaccharide therapy; pyridoxine.

Fig 1:. Therapy options for MPI-CDG, PGM1-CDG and PMM2-CDG

In MPI-CDG, the impaired conversion of fructose-6-P to mannose-6-P due to the defect of the mannose-6-phosphate-isomerase can be addressed therapeutically by supplementation of mannose, which provides additional substrate after the biochemical block. In PMM2-CDG, the conversion of mannose-6-phosphate to mannose-1-phosphate is impaired due to a defect of phosphomannomutase-2, resulting in decreased availability of GDP-mannose, which is used for glycosylation reactions in the endoplasmatic reticulum. Intravenous supplementation of lipophilic mannose-1-P, using liposomes as a carrier, could potentially bypass the metabolic block in PMM2-CDG and hereby, directly correct the glycosylation cascade in the cells. This approach is currently being investigated and might be a therapy option for PMM2-CDG in the future. In PGM1-CDG, defective phosphoglucomutase-1 leads to impaired interconversion of glucose-1-phosphae and glucose-6-phosphate. Supplementation of oral D-galactose bypasses the metabolic block and hereby, directly increases the availability of substrate for glycosylation. As a result of these therapeutical approaches, glycosylation of common proteins (for example, transferrin) is restored.

Fig 2:. Therapy options for SLC35C1-CDG, FUT8-CDG and GFUS-CDG

In SLC35C1-CDG, the defective transporter for GDP-fucose leads to a deficit of GDP-fucose in the Golgi apparatus and hereby, impairs fucosylation of proteins. In FUT8-CDG the enzyme, α-1,6-fucosyltransferase, which adds fucose to glycans in the Golgi apparatus, is defective and due to this defect, fucosylation of serum proteins is impaired. Both defects can be addressed therapeutically by oral supplementation of fucose, which increases the availability of substrate for the defective proteins through the exogenous pathway and hereby, restores fucosylation of glycosylated proteins. GFUS-CDG is due to defective conversion of GDP-mannose to GDP-fucose and leads to impaired de novo synthesis of GDP-fucose. Like in SLC35C1-CDG and FUT8-CDG, increasing the availability of substrate for the defective enzyme by exogenous supplementation might also be a promising approach.

Fig 3:. Therapy options for SLC39A8-CDG, SLC35A2-CDG and TMEM165-CDG

SLC39A8-CDG is due to a defective manganese transporter in the cell membrane, which leads to reduced manganese uptake into the cell and impairment of manganese-dependent galactosyltransferases in the Golgi apparatus. Supplementation of manganese-II-sulfate increases the availability of substrate for the defective transporter, and additional supplementation of D-galactose ensures sufficient availability of galactose to ultimately restore galactosylation. TMEM165-CDG is due to a defective Golgi ion transporter, which leads to disrupted manganese homeostasis in the Golgi apparatus and ultimately, secondary impairment of manganese-dependent galactosyltransferases in the Golgi apparatus. The resulting impaired galactosylation can be addressed by oral supplementation of D-galactose. SLC35A2-CDG is due to a defective UDP-galactose transporter in the Golgi apparatus. The resulting impairment in galactosylation can be improved by oral supplementation of D-galactose, which increases substrate availability for the defective transporter.