RARE DISEASE
PGM1-CDG
PGM1-CDG
PGM1-CDG
Synonyms: CDG syndrome type It, CDG-It, CDG1T, Congenital disorder of glycosylation type 1t, Congenital disorder of glycosylation type It, PGM1-related congenital disorder of glycosylation, Phosphoglucomutase-1 deficiency
Synonyms: CDG syndrome type It, CDG-It, CDG1T, Congenital disorder of glycosylation type 1t, Congenital disorder of glycosylation type It, PGM1-related congenital disorder of glycosylation, Phosphoglucomutase-1 deficiency
Synonyms: CDG syndrome type It, CDG-It, CDG1T, Congenital disorder of glycosylation type 1t, Congenital disorder of glycosylation type It, PGM1-related congenital disorder of glycosylation, Phosphoglucomutase-1 deficiency
Drug discovery
1
drug
With orphan designation
Overview
PGM1-CDG is a rare autosomal recessive disorder disrupting glycosylation and glycogen metabolism due to PGM1 mutations. Clinically, it manifests with cleft palate, hypoglycemia, hepatopathy, myopathy, and cardiomyopathy. Diagnosis combines transferrin glycosylation analysis and genetic testing. D-galactose supplementation (0.3–3 g/kg/day) improves hypoglycemia, coagulation, and glycoprotein profiles but does not resolve cardiac complications [1][2][10][17].
Categories: rare cardiac diseases, rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
110 drug discovery papers about PGM1-CDG, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
110 drug discovery papers about PGM1-CDG, with 1 first-in-class and 1 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).
2026-07-07 | 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.
2026-02-21 | PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes
Abstract Background PGM1-congenital disorder of glycosylation (PGM1-CDG) is frequently associated with cardiomyopathy. Although galactose therapy corrects glycosylation defects, cardiac dysfunction typically persists, suggesting a glycosylation-independent mechanism. Recent evidence of mitochondrial abnormalities in PGM1-deficient human and murine heart, together with the association of PGM1 with the Z-disk protein LDB3 (ZASP/Cypher), suggests a critical role for PGM1 in cardiomyocyte structural and energetic homeostasis. We hypothesized that PGM1-related cardiomyopathy arises from a glycosylation-independent disruption of Z-disk–mitochondrial coupling driven by loss of PGM1–LDB3 interactions, resulting in mitochondrial energy failure and impaired contractile function. Methods Induced pluripotent stem cell–derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays. Results PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro. In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy. Conclusion Our data suggests PGM1 is key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction. Graphical Abstract
2025-11-28 | SLC35A2-Related Brain Disorders: Genetics, Pathophysiology, and Therapeutic Insights
SLC35A2 encodes the Golgi uridine diphosphate galactose transporter, which is essential for glycosylation of glycoproteins and glycolipids. Variants in this gene, either germline or somatic, have emerged as causes of diverse neurological disorders ranging from congenital disorders of glycosylation (SLC35A2-CDG) to focal cortical malformations such as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). This review summarizes the molecular function of SLC35A2, clinical phenotypes of congenital and somatic variants, insights from functional assays and animal models, and therapeutic perspectives including galactose supplementation and precision medicine. We aim to provide an integrative synthesis of human genetics, neuropathology, glycomics, and translational approaches.
2025-11-03 | Novel PGM1 Mutation in Congenital Disorder of Glycosylation Type 1T: A Case Report of Liver Failure and Myopathy.
BACKGROUND Congenital disorders of glycosylation (CDG) are rare, inherited metabolic conditions caused by defects in glycoprotein synthesis. CDG Type 1T, associated with mutations in the phosphoglucomutase 1 (PGM1) gene, often presents with hepatic dysfunction, developmental delay, and multisystem involvement. Due to clinical overlap with other metabolic disorders, misdiagnosis is common, leading to delayed treatment. CASE REPORT We report a 20-month-old boy, born to consanguineous parents, who initially received a misdiagnosis of galactosemia following abnormal newborn screening. Despite dietary modifications, he developed persistent transaminitis, coagulopathy, hypotonia, and delayed motor milestones. Further evaluation revealed abnormal carbohydrate-deficient transferrin analysis, and whole exome sequencing identified a homozygous PGM1 variant of uncertain significance, supporting CDG Type 1T diagnosis. Liver biopsy demonstrated steatosis with bridging portal fibrosis. The patient was started on oral D-galactose supplementation (1.5 g/kg/day). Over a 51-day follow-up period, liver enzymes improved markedly, with AST declining from 1980 to 385 U/L and ALT from 695 to 210 U/L, alongside normalization of coagulation profiles. Muscle enzyme response was partial, with creatine kinase levels remaining mildly elevated, reflecting differential therapeutic effects across tissues. CONCLUSIONS This case underscores the diagnostic challenges of CDG Type 1T and emphasizes the importance of combining biochemical markers and genetic sequencing to achieve timely diagnosis. The identified PGM1 variant, although classified as a variant of uncertain significance, was strongly supported by clinical and biochemical findings. Significant hepatic improvement with D-galactose highlights the therapeutic potential of early targeted supplementation, although incomplete muscular response indicates the need for ongoing follow-up and exploration of adjunctive therapies.
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).
2026-07-07 | 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.
2026-02-21 | PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes
Abstract Background PGM1-congenital disorder of glycosylation (PGM1-CDG) is frequently associated with cardiomyopathy. Although galactose therapy corrects glycosylation defects, cardiac dysfunction typically persists, suggesting a glycosylation-independent mechanism. Recent evidence of mitochondrial abnormalities in PGM1-deficient human and murine heart, together with the association of PGM1 with the Z-disk protein LDB3 (ZASP/Cypher), suggests a critical role for PGM1 in cardiomyocyte structural and energetic homeostasis. We hypothesized that PGM1-related cardiomyopathy arises from a glycosylation-independent disruption of Z-disk–mitochondrial coupling driven by loss of PGM1–LDB3 interactions, resulting in mitochondrial energy failure and impaired contractile function. Methods Induced pluripotent stem cell–derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays. Results PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro. In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy. Conclusion Our data suggests PGM1 is key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction. Graphical Abstract
2025-11-28 | SLC35A2-Related Brain Disorders: Genetics, Pathophysiology, and Therapeutic Insights
SLC35A2 encodes the Golgi uridine diphosphate galactose transporter, which is essential for glycosylation of glycoproteins and glycolipids. Variants in this gene, either germline or somatic, have emerged as causes of diverse neurological disorders ranging from congenital disorders of glycosylation (SLC35A2-CDG) to focal cortical malformations such as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). This review summarizes the molecular function of SLC35A2, clinical phenotypes of congenital and somatic variants, insights from functional assays and animal models, and therapeutic perspectives including galactose supplementation and precision medicine. We aim to provide an integrative synthesis of human genetics, neuropathology, glycomics, and translational approaches.
2025-11-03 | Novel PGM1 Mutation in Congenital Disorder of Glycosylation Type 1T: A Case Report of Liver Failure and Myopathy.
BACKGROUND Congenital disorders of glycosylation (CDG) are rare, inherited metabolic conditions caused by defects in glycoprotein synthesis. CDG Type 1T, associated with mutations in the phosphoglucomutase 1 (PGM1) gene, often presents with hepatic dysfunction, developmental delay, and multisystem involvement. Due to clinical overlap with other metabolic disorders, misdiagnosis is common, leading to delayed treatment. CASE REPORT We report a 20-month-old boy, born to consanguineous parents, who initially received a misdiagnosis of galactosemia following abnormal newborn screening. Despite dietary modifications, he developed persistent transaminitis, coagulopathy, hypotonia, and delayed motor milestones. Further evaluation revealed abnormal carbohydrate-deficient transferrin analysis, and whole exome sequencing identified a homozygous PGM1 variant of uncertain significance, supporting CDG Type 1T diagnosis. Liver biopsy demonstrated steatosis with bridging portal fibrosis. The patient was started on oral D-galactose supplementation (1.5 g/kg/day). Over a 51-day follow-up period, liver enzymes improved markedly, with AST declining from 1980 to 385 U/L and ALT from 695 to 210 U/L, alongside normalization of coagulation profiles. Muscle enzyme response was partial, with creatine kinase levels remaining mildly elevated, reflecting differential therapeutic effects across tissues. CONCLUSIONS This case underscores the diagnostic challenges of CDG Type 1T and emphasizes the importance of combining biochemical markers and genetic sequencing to achieve timely diagnosis. The identified PGM1 variant, although classified as a variant of uncertain significance, was strongly supported by clinical and biochemical findings. Significant hepatic improvement with D-galactose highlights the therapeutic potential of early targeted supplementation, although incomplete muscular response indicates the need for ongoing follow-up and exploration of adjunctive therapies.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for PGM1-CDG.
1 orphan drug designation for PGM1-CDG.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
D-Galactose | small molecules | FDA | 2019-01-14 | — | AUG Therapeutics, LLC |
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