RARE DISEASE
Congenital disorder of glycosylation
Congenital disorder of glycosylation
Congenital disorder of glycosylation
Synonyms: CDG, Carbohydrate deficient glycoprotein syndrome
Synonyms: CDG, Carbohydrate deficient glycoprotein syndrome
Synonyms: CDG, Carbohydrate deficient glycoprotein syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Congenital Disorders of Glycosylation (CDG) are a genetically diverse group of over 130 inherited metabolic disorders caused by defects in protein and lipid glycosylation pathways. These multisystem conditions commonly present with developmental delay, hypotonia, failure to thrive, coagulopathy, and neurological abnormalities. Diagnosis relies on transferrin isoelectric focusing, glycan analysis, and genomic sequencing. While most subtypes lack curative treatments, targeted therapies (e.g., substrate/cofactor supplementation) exist for specific forms (e.g., MPI-CDG, PGM1-CDG).
Therapies
Causative: Mannose (MPI-CDG), galactose (PGM1-CDG, SLC35A2-CDG), fucose (SLC35C1-CDG), and manganese (TMEM165-CDG) supplementation [3][5][6].
Symptomatic: Anticonvulsants, albumin infusions, and hormone replacement [5][15].
Emerging: Pharmacological chaperones (e.g., epalrestat) and gene therapy under investigation [3][12].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
493 drug discovery papers about Congenital disorder of glycosylation, with 1 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
493 drug discovery papers about Congenital disorder of glycosylation, with 1 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-07 | Hypoglycosylation lowers the mechanical activation threshold of Piezo1 and enhances cortical neuronal mechanotransduction: implications for PMM2-CDG
Abstract Piezo1 is a mechanically activated cation channel whose N-linked glycans support protein maturation and plasma membrane trafficking, but their contribution to mechanical gating is unknown. We asked whether hypoglycosylation alters Piezo1 mechanosensitivity and cortical neuronal mechanotransduction, with potential relevance to neurological manifestations of congenital disorders of glycosylation (CDG). Human Piezo1 was studied in HEK293 cells after mutation of two conserved cap-domain N-glycosylation sites or inhibition of N-glycan maturation with swainsonine or kifunensine. Mechanically activated currents were recorded by cell-attached patch-clamp during incremental negative-pressure pulses, whereas Ca 2+ responses were measured during uniaxial stretch. Piezo1 abundance, synaptic localisation and stretch-evoked Ca 2+ signals were also examined in primary mouse cortical neurons. On poly-L-lysine, N2293Q or N2330Q shifted the pressure-response relationship towards lower activating pressures without changing maximal current or inactivation kinetics. This effect was absent on collagen. Swainsonine and kifunensine reduced mature Piezo1 glycosylation and lowered the mechanical activation threshold. Hypoglycosylation enhanced Ca 2+ entry during submaximal stretch in HEK293 cells. In cortical neurons, inhibition of glycan maturation increased somatic Piezo1 immunoreactivity without changing its association with synaptic markers, and potentiated Ca 2+ responses to both the Piezo1 activator Yoda1 and submaximal stretch. Thus, mature N-glycans and the extracellular adhesive environment jointly set Piezo1’s mechanical activation threshold rather than merely regulating biosynthesis and trafficking. These findings establish glycosylation-mechanics coupling as a determinant of neuronal force sensing and suggest that, by facilitating Piezo1 recruitment, defective glycosylation may increase cortical vulnerability to mechanical stress, potentially contributing to head trauma-triggered neurological episodes in phosphomannomutase 2 deficiency (PMM2-CDG). Key points Piezo1 channels convert mechanical forces into electrical and calcium signals. N-linked glycans support channel trafficking to the plasma membrane, but whether they tune the force needed for Piezo1 activation was unknown. Mutating either of two conserved N-glycosylation sites in Piezo1 cap domain, or pharmacologically restricting N-glycan maturation, lowered channel’s mechanical activation threshold without changing maximal current or inactivation. This sensitisation depended on the adhesive substrate (occurred on poly-L-lysine but not collagen), and was most evident during submaximal stretch, showing that glycosylation and the extracellular mechanical environment jointly determine Piezo1 force sensing. In mouse cortical neurons, impaired N-glycan maturation increased somatic Piezo1 abundance and enhanced Ca 2+ responses to its chemical activator Yoda1 and stretch, without changing synaptic localisation. By allowing weak mechanical inputs to recruit Piezo1 more effectively, defective glycosylation may increase cortical responses to mechanical stress and help explain susceptibility to head trauma-triggered neurological episodes in phosphomannomutase 2 deficiency (PMM2-CDG).
2026-07-29 | Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation
Abstract Background Steroid 5 alpha-reductase 3-related congenital disorder of glycosylation (SRD5A3-CDG) is a rare inherited disease characterized by neurological dysfunction, including ataxia, as well as developmental and visual impairments, with no approved treatments. The disease is caused by defects in dolichol biosynthesis, a pathway essential for protein glycosylation. However, the lack of suitable in vivo models has limited both mechanistic insight and therapeutic development. Methods We generated a Caenorhabditis elegans model carrying a patient-relevant loss-of-function mutation and performed a motility-based phenotypic drug repurposing screen to identify compounds that improve disease-relevant phenotypes. Lead compounds were evaluated in behavioral, neuronal, and metabolomic assays in worms and in fibroblasts from four individuals with SRD5A3-CDG. Results Here we show that SRD5A3-deficient worms exhibit developmental delay, neuronal dysfunction, and metabolic alterations consistent with dysregulation of the mevalonate pathway. The screen identifies multiple classes of compounds that improve motility, including the cholesterol-lowering drug atorvastatin. Atorvastatin improves multiple disease-relevant phenotypes in the worm model. In patient-derived fibroblasts, treatment partially restores the balance between polyprenol and dolichol, which is disrupted in SRD5A3-CDG. Conclusions These findings establish an in vivo model of SRD5A3-CDG and identify modulation of the mevalonate pathway as a potential therapeutic strategy. The results support further investigation of atorvastatin as a repurposed treatment and demonstrate an approach for combining model organism screening with human cell validation to accelerate rare disease drug discovery.
2026-07-10 | B4GALT5 deficiency impairs glycosphingolipid biosynthesis: a new Congenital Disorder of Glycosylation?
Lactosylceramide is a glycosphingolipid precursor synthesized by two dedicated galactosyltransferases, B4GALT5 and B4GALT6. The specific roles of B4GALT5 and B4GALT6 in humans have not yet been clearly defined. Here, we report the first human case with bi-allelic loss-of-function variants in B4GALT5, suggesting that intact B4GALT5 activity is indispensable for normal glycosphingolipid biosynthesis and human development. We identified bi-allelic variants in the B4GALT5 gene in a child presenting with microcephaly, mild cognitive impairment, and bilateral cataracts. B4GALT5/6 double KO cells transfected with B4GALT5 carrying either of the variants identified in the patient lacked lactosylceramide synthase activity and failed to produce glycosphingolipids. In-silico analyses predicted decreased protein stability and impaired UDP-Gal binding for both B4GALT5 variants. Together, these findings indicate that both variants result in deficient B4GALT5 activity, leaving B4GALT6 as the sole source of lactosylceramide synthase activity. Consistent with this, patient plasma and fibroblasts exhibited an approximately 80% reduction in glycosphingolipid levels compared with healthy controls. Unexpectedly, when expressed in model cells human B4GALT6 displayed lower expression and lower catalytic activity, than human B4GALT5, raising questions about its capacity to compensate for B4GALT5 deficiency. In conclusion, we identified a potential new congenital disorder of glycosylation caused by deficient lactosylceramide synthase activity that may be insufficient to support glycosphingolipids synthesis at levels required for normal brain function.
2026-07-07 | Structural insights into mutated human phosphoglucomutase 1 (PGM1) using computational approaches
The phosphoglucomutase 1 (PGM1) enzyme plays a critical role in metabolism and glycosylation in the human body. PGM1 has been linked to multiple disease phenotypes, including the inherited metabolic disorder known as congenital disorders of glycosylation (CDGs). Numerous clinical studies have shown that mutations in key regions of the PGM1 gene affect catalytic activity and induce folding defects of the enzyme. To delve into molecular changes at the supramolecular level, the structural, stability, and other features of PGM1 variants (T19A, N38Y, and D62H) were studied in the present work. To this end, molecular dynamics (MD) simulation at a long timescale (500 ns) was carried out. Parameters such as root-mean-square deviation (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen bonds, and free energy landscape (FEL) were studied and compared with those of the wild-type PGM1. It was noted that mutations 19 A, N38Y, and D62H significantly alter the protein’s structural behavior, causing increased flexibility, reduced stability, and compactness.
2026-07-02 | Effects of Deficient Glycosylation and Deglycosylation on Sperm Condition in Zebrafish ( Danio rerio )
Abstract Congenital disorders of glycosylation and deglycosylation are rare, serious, and lethal disorders afflicting humans. CDGs and CDDGs result in loss of function enzymes which fail to build or break down oligosaccharides on proteins. This can produce protein aggregates and, in turn, reactive oxygen species that harm the cell eventually leading to autophagy and apoptosis. Because sperm contain high concentrations of polyunsaturated fatty acids, they are especially sensitive to these effects, which is understood as one of the leading factors in human male infertility. Sperm are developed in zebrafish similarly to humans and are useful models to examine human reproductive health, as well as genetic disorders. The combination of these advantages makes the analysis of sperm from zebrafish with heterozygous ALG1 or DPAGT1 CDGs or the NGLY1 CDDG suitable. Analysis of sperm concentration, motility, status, viability, and hypoosmotic swelling demonstrated the effects of these disorders on sperm quality. Results showed a significant decrease in sperm concentration, motility, and hypoosmotic swelling for all mutant zebrafish compared to the wild type. This suggests that CDGs and CDDGs influence the amount of sperm produced, the percentage of sperm cells that are mobile, and the integrity of the plasma membrane.
2026-08-07 | Hypoglycosylation lowers the mechanical activation threshold of Piezo1 and enhances cortical neuronal mechanotransduction: implications for PMM2-CDG
Abstract Piezo1 is a mechanically activated cation channel whose N-linked glycans support protein maturation and plasma membrane trafficking, but their contribution to mechanical gating is unknown. We asked whether hypoglycosylation alters Piezo1 mechanosensitivity and cortical neuronal mechanotransduction, with potential relevance to neurological manifestations of congenital disorders of glycosylation (CDG). Human Piezo1 was studied in HEK293 cells after mutation of two conserved cap-domain N-glycosylation sites or inhibition of N-glycan maturation with swainsonine or kifunensine. Mechanically activated currents were recorded by cell-attached patch-clamp during incremental negative-pressure pulses, whereas Ca 2+ responses were measured during uniaxial stretch. Piezo1 abundance, synaptic localisation and stretch-evoked Ca 2+ signals were also examined in primary mouse cortical neurons. On poly-L-lysine, N2293Q or N2330Q shifted the pressure-response relationship towards lower activating pressures without changing maximal current or inactivation kinetics. This effect was absent on collagen. Swainsonine and kifunensine reduced mature Piezo1 glycosylation and lowered the mechanical activation threshold. Hypoglycosylation enhanced Ca 2+ entry during submaximal stretch in HEK293 cells. In cortical neurons, inhibition of glycan maturation increased somatic Piezo1 immunoreactivity without changing its association with synaptic markers, and potentiated Ca 2+ responses to both the Piezo1 activator Yoda1 and submaximal stretch. Thus, mature N-glycans and the extracellular adhesive environment jointly set Piezo1’s mechanical activation threshold rather than merely regulating biosynthesis and trafficking. These findings establish glycosylation-mechanics coupling as a determinant of neuronal force sensing and suggest that, by facilitating Piezo1 recruitment, defective glycosylation may increase cortical vulnerability to mechanical stress, potentially contributing to head trauma-triggered neurological episodes in phosphomannomutase 2 deficiency (PMM2-CDG). Key points Piezo1 channels convert mechanical forces into electrical and calcium signals. N-linked glycans support channel trafficking to the plasma membrane, but whether they tune the force needed for Piezo1 activation was unknown. Mutating either of two conserved N-glycosylation sites in Piezo1 cap domain, or pharmacologically restricting N-glycan maturation, lowered channel’s mechanical activation threshold without changing maximal current or inactivation. This sensitisation depended on the adhesive substrate (occurred on poly-L-lysine but not collagen), and was most evident during submaximal stretch, showing that glycosylation and the extracellular mechanical environment jointly determine Piezo1 force sensing. In mouse cortical neurons, impaired N-glycan maturation increased somatic Piezo1 abundance and enhanced Ca 2+ responses to its chemical activator Yoda1 and stretch, without changing synaptic localisation. By allowing weak mechanical inputs to recruit Piezo1 more effectively, defective glycosylation may increase cortical responses to mechanical stress and help explain susceptibility to head trauma-triggered neurological episodes in phosphomannomutase 2 deficiency (PMM2-CDG).
2026-07-29 | Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation
Abstract Background Steroid 5 alpha-reductase 3-related congenital disorder of glycosylation (SRD5A3-CDG) is a rare inherited disease characterized by neurological dysfunction, including ataxia, as well as developmental and visual impairments, with no approved treatments. The disease is caused by defects in dolichol biosynthesis, a pathway essential for protein glycosylation. However, the lack of suitable in vivo models has limited both mechanistic insight and therapeutic development. Methods We generated a Caenorhabditis elegans model carrying a patient-relevant loss-of-function mutation and performed a motility-based phenotypic drug repurposing screen to identify compounds that improve disease-relevant phenotypes. Lead compounds were evaluated in behavioral, neuronal, and metabolomic assays in worms and in fibroblasts from four individuals with SRD5A3-CDG. Results Here we show that SRD5A3-deficient worms exhibit developmental delay, neuronal dysfunction, and metabolic alterations consistent with dysregulation of the mevalonate pathway. The screen identifies multiple classes of compounds that improve motility, including the cholesterol-lowering drug atorvastatin. Atorvastatin improves multiple disease-relevant phenotypes in the worm model. In patient-derived fibroblasts, treatment partially restores the balance between polyprenol and dolichol, which is disrupted in SRD5A3-CDG. Conclusions These findings establish an in vivo model of SRD5A3-CDG and identify modulation of the mevalonate pathway as a potential therapeutic strategy. The results support further investigation of atorvastatin as a repurposed treatment and demonstrate an approach for combining model organism screening with human cell validation to accelerate rare disease drug discovery.
2026-07-10 | B4GALT5 deficiency impairs glycosphingolipid biosynthesis: a new Congenital Disorder of Glycosylation?
Lactosylceramide is a glycosphingolipid precursor synthesized by two dedicated galactosyltransferases, B4GALT5 and B4GALT6. The specific roles of B4GALT5 and B4GALT6 in humans have not yet been clearly defined. Here, we report the first human case with bi-allelic loss-of-function variants in B4GALT5, suggesting that intact B4GALT5 activity is indispensable for normal glycosphingolipid biosynthesis and human development. We identified bi-allelic variants in the B4GALT5 gene in a child presenting with microcephaly, mild cognitive impairment, and bilateral cataracts. B4GALT5/6 double KO cells transfected with B4GALT5 carrying either of the variants identified in the patient lacked lactosylceramide synthase activity and failed to produce glycosphingolipids. In-silico analyses predicted decreased protein stability and impaired UDP-Gal binding for both B4GALT5 variants. Together, these findings indicate that both variants result in deficient B4GALT5 activity, leaving B4GALT6 as the sole source of lactosylceramide synthase activity. Consistent with this, patient plasma and fibroblasts exhibited an approximately 80% reduction in glycosphingolipid levels compared with healthy controls. Unexpectedly, when expressed in model cells human B4GALT6 displayed lower expression and lower catalytic activity, than human B4GALT5, raising questions about its capacity to compensate for B4GALT5 deficiency. In conclusion, we identified a potential new congenital disorder of glycosylation caused by deficient lactosylceramide synthase activity that may be insufficient to support glycosphingolipids synthesis at levels required for normal brain function.
2026-07-07 | Structural insights into mutated human phosphoglucomutase 1 (PGM1) using computational approaches
The phosphoglucomutase 1 (PGM1) enzyme plays a critical role in metabolism and glycosylation in the human body. PGM1 has been linked to multiple disease phenotypes, including the inherited metabolic disorder known as congenital disorders of glycosylation (CDGs). Numerous clinical studies have shown that mutations in key regions of the PGM1 gene affect catalytic activity and induce folding defects of the enzyme. To delve into molecular changes at the supramolecular level, the structural, stability, and other features of PGM1 variants (T19A, N38Y, and D62H) were studied in the present work. To this end, molecular dynamics (MD) simulation at a long timescale (500 ns) was carried out. Parameters such as root-mean-square deviation (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen bonds, and free energy landscape (FEL) were studied and compared with those of the wild-type PGM1. It was noted that mutations 19 A, N38Y, and D62H significantly alter the protein’s structural behavior, causing increased flexibility, reduced stability, and compactness.
2026-07-02 | Effects of Deficient Glycosylation and Deglycosylation on Sperm Condition in Zebrafish ( Danio rerio )
Abstract Congenital disorders of glycosylation and deglycosylation are rare, serious, and lethal disorders afflicting humans. CDGs and CDDGs result in loss of function enzymes which fail to build or break down oligosaccharides on proteins. This can produce protein aggregates and, in turn, reactive oxygen species that harm the cell eventually leading to autophagy and apoptosis. Because sperm contain high concentrations of polyunsaturated fatty acids, they are especially sensitive to these effects, which is understood as one of the leading factors in human male infertility. Sperm are developed in zebrafish similarly to humans and are useful models to examine human reproductive health, as well as genetic disorders. The combination of these advantages makes the analysis of sperm from zebrafish with heterozygous ALG1 or DPAGT1 CDGs or the NGLY1 CDDG suitable. Analysis of sperm concentration, motility, status, viability, and hypoosmotic swelling demonstrated the effects of these disorders on sperm quality. Results showed a significant decrease in sperm concentration, motility, and hypoosmotic swelling for all mutant zebrafish compared to the wild type. This suggests that CDGs and CDDGs influence the amount of sperm produced, the percentage of sperm cells that are mobile, and the integrity of the plasma membrane.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Congenital disorder of glycosylation.
2 orphan drug designations for Congenital disorder of glycosylation.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
repirinast | small molecules | FDA | 2024-11-07 | — | bloom for a cure LLC |
L-fucose | small molecules | FDA | 2019-01-14 | — | AUG Therapeutics, LLC |
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