Treatment Options in Congenital Disorders of Glycosylation

Abstract

Despite advances in the identification and diagnosis of congenital disorders of glycosylation (CDG), treatment options remain limited and are often constrained to symptomatic management of disease manifestations. However, recent years have seen significant advances in treatment and novel therapies aimed both at the causative defect and secondary disease manifestations have been transferred from bench to bedside. In this review, we aim to give a detailed overview of the available therapies and rising concepts to treat these ultra-rare diseases.

Keywords: chaperone; cofactor; congenital disorder of glycosylation; drug repurposing; glycosylation; substrate supplementation; treatment.

FIGURE 1

Glycosylation analysis of serum transferrin using isoelectric focusing and high-performance liquid chromatography. Isoelectric focusing (IEF) of serum transferrin has traditionally been used to diagnose congenital disorders of N-glycosylation. The test separates transferrin isoforms according to their negative charge that is dependent on the amount of sialic acid residues on glycan chains, with each sialic acid residue corresponding to a negative charge. Currently, alternative methods such as high-performance liquid chromatography (HPLC) are being favored for their ease of use and ability to generate quantitative results for transferrin isoforms. (A) A normal glycosylation profile in IEF of serum transferrin with tetrasialo-transferrin (4-) representing the major fraction of transferrin isoforms. To the right, the corresponding HPLC curve can be seen, giving the area % for the varying transferrin subtypes (pentasialo-transferrin 4.97%, tetrasialo-transferrin 92.44%, trisialo-transferrin 1.94%, and disialo-transferrin 0.65%). (B) Impaired transferrin glycosylation seen in a PMM2-CDG patient, with decreased tetrasialo-transferrin and increased di-(2-) and monosialo-(1-)transferrin proportions (type I CDG pattern). HPLC identified pentasialo-transferrin (4.62%), tetrasialo-transferrin (68.02%), trisialo-transferrin (0.89%), disialo-transferrin (21.36%), and asialo-transferrin (5.1%). (C) In a COG6-CDG patient, increased proportions of tri- (3-), di- (2-), and monosialo-transferrin (1-) are seen in IEF. HPLC detected pentasialo-transferrin (5.2%), tetrasialo-transferrin (69.16%), trisialo-transferrin (22.03%), disialo-transferrin (2.99%), and monosialo-transferrin (0.62%). Reference intervals for HPLC of serum transferrin at our laboratory: Pentasialo (5-) 2.6–10.2%, tetrasialo (4-) 85.7–94.0%, trisialo (3-) 1.16–6.36%, disialo (2-) 0.38–1.82%, monosialo (1-) 0%, asialo (0-) 0%.

FIGURE 2

Therapeutic concepts for congenital disorders of glycosylation. (A) Substrate supplementation aims at overcoming the impaired transport process or enzymatic reaction by increasing the concentration of the substrate of the respective reaction. One such treatment is galactose supplementation for SLC35A2-CDG, where oral supplementation of galactose (yellow circle) increases UDP-galactose supplies and thus transport across the defective UDP-galactose transporter SLC35A2. (B) In SLC39A8-CDG, defects in SLC39A8 lead to a deficiency in manganese (Mn²⁺). Lack of this cofactor impairs the function of galactosyltransferases (GalT). Cofactor supplementation leads to an improved GalT function and thus normalized glycosylation. (C) Mutated and subsequentially misfolded enzymes are either degraded or impaired in function. Specific mutations in PMM2 result in misfolded phosphomannomutase 2 (A). Pharmacological chaperones (in this case epalrestat) bind and stabilize the affected enzyme, leading to increased enzyme activity and thus improved glycosylation (B).

FIGURE 3

Mannose therapy in MPI-CDG. (A) Mutations in MPI lead to an impaired function of phosphomannose isomerase (PMI), thus hindering the interconversion of fructose-6-phosphate (Fru-6-P) to mannose-6-phosphate (Man-6-P). (B) The oral supplementation of mannose increases the available Man-6-P following conversion of mannose (Man) by hexokinase (HK). After conversion of Man-6-P to mannose-1-phosphate (Man-1-P) by phosphomannomutase 2 (PMM2), conversion into guanosine diphosphate-mannose (GDP-Man). This can be used in N-glycosylation.

FIGURE 4

Galactose therapy in PGM1-CDG. (A) A defect in PGM1 hinders conversion of glucose-1-phosphate (Glu-1-P) to glucose-6-phosphate (Glu-6-P), thus impairing hepatic glucose release. Similarly, the reverse reaction in which Glu-6-P is converted to Glu-1-P, which can serve as a substrate for UDP-glucose production by UDP-glucose pyrophosphorylase (UGP) for glycogen synthesis or glycosylation, is impaired. (B) Supplemented galactose is transformed to UDP-galactose (UDP-Gal) by galactose-1-phosphate uridyltransferase (GALT). UDP-Gal can serve both in glycosylation and as a substrate for UDP-galactose epimerase (GALE), supplying UDP-Gal for glycogen metabolism. (C) Transferrin IEF profiles during galactose substitution over 140 days in PGM1-CDG. Compared to controls, PGM1-CDG shows a characteristic, “ladder-like” pattern in IEF (PGM1-CDG, T₀). Following 20 weeks of galactose substitution at a dose of 1 g/kg bodyweight/day, significant improvement with reduced abnormal transferrin isoforms was observed (PGM1-CDG, T₁₄₀) (4 – tetrasialo-transferrin, 3 – trisialo-transferrin, 2 – disialo-transferrin, 1 – monosialo-transferrin, 0 – asialo-transferrin).

FIGURE 5

Mannose supplementation in PMM2-CDG. (A) In PMM2-CDG, the conversion of mannose-6-phosphate (Man-6-P) to mannose-1-phosphate (Man-1-P) by phosphomannomutase 2 (PMM2) is impaired due to mutations in PMM2. (B) Findings for mannose supplementation in PMM2-CDG have been inconsistent. In a subgroup of patients, significant improvement of serum transferrin glycosylation can be achieved with oral supplementation of mannose. Of note, these changes occur after several months or even years and have been shown to be reversible if mannose substitution is discontinued. PMM2-CDG I and II – Pretherapeutic samples from the same patient; PMM2-CDG III–VI – Samples after 1, 2, 3, and 4 years of mannose substitution at a dose of 1 g/kg bodyweight/day (HK, hexokinase; Glu-6-P, glucose-6-phosphate; PGI, glucose-6-phosphate isomerase; Fru-6-P, fructose-6-phosphate; PMI, phosphomannose isomerase; GMPPA, Mannose-1-phosphate guanyltransferase alpha; GMPPB, Mannose-1-phosphate guanyltransferase beta).