RARE DISEASE
PMM2-CDG
PMM2-CDG
PMM2-CDG
Synonyms: CDG syndrome type Ia, CDG-Ia, CDG1A, Carbohydrate deficient glycoprotein syndrome type Ia, Congenital disorder of glycosylation type 1a, Congenital disorder of glycosylation type Ia, Phosphomannomutase 2 deficiency
Synonyms: CDG syndrome type Ia, CDG-Ia, CDG1A, Carbohydrate deficient glycoprotein syndrome type Ia, Congenital disorder of glycosylation type 1a, Congenital disorder of glycosylation type Ia, Phosphomannomutase 2 deficiency
Synonyms: CDG syndrome type Ia, CDG-Ia, CDG1A, Carbohydrate deficient glycoprotein syndrome type Ia, Congenital disorder of glycosylation type 1a, Congenital disorder of glycosylation type Ia, Phosphomannomutase 2 deficiency
Drug discovery
4
drugs
With orphan designations
Overview
PMM2-CDG is the most common congenital disorder of glycosylation, caused by autosomal recessive mutations in PMM2, leading to impaired synthesis of mannose-1-phosphate and defective N-glycosylation. This multisystem disorder presents with cerebellar hypoplasia, hypotonia, developmental delay, coagulopathy, inverted nipples, and failure to thrive. Severity varies from lethal infantile forms to milder adult-onset neuropathy and hypergonadotropic hypogonadism in females [1][4][6].
Burden
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare skin diseases
Research Papers
146 drug discovery papers about PMM2-CDG, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
146 drug discovery papers about PMM2-CDG, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-02-22 | A founder variant in Tunisian PMM2-CDG patients: An integrated clinical, radiological, biochemical, and genetic study.
PMM2-CDG is the most common congenital disorder of glycosylation, characterized by a broad phenotypic spectrum involving the nervous system and multiple other organ systems. The disorder is caused by biallelic variants in the PMM2 gene, leading to impaired glycosylation of proteins. Our objective was to provide a detailed clinical characterization and define the mutational spectrum of PMM2-CDG in the Tunisian population. We conducted a retrospective study on patients with genetically confirmed PMM2-CDG, followed between 2005 and 2024. Ten patients from six unrelated Tunisian families were enrolled. All presented with neurological symptoms, including psychomotor delay (10/10), cerebellar ataxia (9/10) and strabismus (9/10). Brain MRI revealed cerebellar atrophy in all patients. Dysmorphic features were common including almond-shaped eyes (9/10), large mouth (6/10), and thin upper lip (6/10). Skeletal anomalies were observed in 9/10 patients. Peripheral neuropathy was confirmed in 6/7 patients. Laboratory analyses revealed elevated transaminases (6/10), hypocholesterolemia (7/10), elevated LDH (7/10), hypoalbuminemia (2/6), and IgA deficiency (3/5). Renal anomalies included hyperechogenicity (2/9) and a duplicated collecting system (1/9). Genetic analysis revealed a homozygous variant NM_000303.3(PMM2): c.395 T > C; p.(Ile132Thr) in all patients. Haplotype analysis of the PMM2 locus showed that all 6 families shared an identical allele. In conclusion, this is the first study to characterize the clinical and genetic profile of PMM2-CDG in the Tunisian population. Despite a shared genotype, patients exhibited moderate neurological phenotypes with inter- and intrafamilial variability. The recurrent homozygous c.395 T > C; p.(Ile132Thr) variant and identical haplotype confirm a founder effect in the Tunisian population.
2026-01-16 | PMM2-CDG and the Role of Liver Transplantation as a Long-Term Solution: A Case Report.
Phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG) is the most common congenital disorder of glycosylation, affecting protein glycosylation across multiple organ systems. Hepatic involvement may range from isolated elevations in liver transaminases to end-stage liver disease. Reported outcomes of liver transplantation as a treatment modality are sparse. We describe one of the first reported cases of liver transplantation in a child with PMM2-CDG and interim post-transplant outcomes. This patient was diagnosed at 4 months of age after presenting with failure to thrive, lipodystrophy, hypotonia, developmental delay, elevated transaminases, hypoalbuminemia, and coagulopathy. He developed cirrhosis and portal hypertension as well as sequelae of poor protein glycosylation. All these included coagulopathy, protein-losing enteropathy, and refractory ascites requiring serial intravenous fresh frozen plasma and furosemide. He ultimately underwent a liver transplant, after which his ascites resolved. Post-transplant, he developed new-onset recurrent pericardial effusions, suspected to be from a viral etiology versus extrahepatic manifestations of PMM2-CDG, and elevated transaminases following transplantation. Liver transplantation may offer clinical benefit in PMM2-CDG with severe hepatic involvement, including resolution of ascites and improved quality of life, due to its potential to restore liver glycosylation function. However, this is only a partial correction as persistent extrahepatic manifestations underscore the need for further research into transplant outcomes and systemic disease progression in CDG.
2026-01-01 | Modeling human PMM2-CDG in medaka to understand systemic effects of hypoglycosylation on development
Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases caused by mutations in the enzymes involved in glycosylation. To date, no conclusive pathogenic mechanism is linked to the disease and there are only limited therapeutic options available. The most common form of CDG is caused by compound heterozygous hypomorphic alleles of the cytosolic enzyme Phosphomannomutase 2 (PMM2), leading to global protein hypoglycosylation and a multiorgan phenotype in patients. Complete loss-of-function mutations in the essential protein are incompatible with life. Patients that survive carry mutations that lead to reduced enzyme activity of PMM2. PMM2 plays a crucial role at the basis of the glycosylation cascade in the endoplasmic reticulum by providing the essential mannose precursor required for the three glycosylation routes N-glycosylation, O- and C-mannosylation. The entire glycosylation machinery is evolutionarily highly conserved which allows generating translational models in other organisms. The small teleost medaka (Oryzias latipes) offers a great advantage as model organism to investigate the early embryogenesis through the extrauterine and transparent developing embryos. To understand acute effects of Pmm2 loss on development and disease progression, I have created translational models that mimic the reduced residual enzyme activity of PMM2-CDG patients. I followed two routes to investigate the role of PMM2 on development: establish a conditional knockdown system for acute Pmm2 interference at the protein level and patient-based genetic models by precision genome editing in medaka. For the conditional knockdown in medaka, I applied an inducible degron system to selectively degrade Pmm2-GFP, mimicking reduced enzyme activity. To generate patient-based pmm2 alleles, I used canonical base editing to generate the p.C139R mutation and a deletion variant. Further, I developed and carefully examined a novel two step one-shot base editing approach termed “inception”. Inception introduces a new binding site for a second base editing event that subsequently leads to the anticipated edit. With inception I created one of the common patient mutations p.F119L. Depending on the generated alleles, different pmm2 variants resulted in varying enzymatic activity in medaka, phenocopied the patient symptoms and caused hypoglycosylation of proteins. Bottom-up proteomics revealed molecular changes already present before the onset of multisystemic phenotypes, affecting particularly mRNA processing and eye development.
2026-02-22 | A founder variant in Tunisian PMM2-CDG patients: An integrated clinical, radiological, biochemical, and genetic study.
PMM2-CDG is the most common congenital disorder of glycosylation, characterized by a broad phenotypic spectrum involving the nervous system and multiple other organ systems. The disorder is caused by biallelic variants in the PMM2 gene, leading to impaired glycosylation of proteins. Our objective was to provide a detailed clinical characterization and define the mutational spectrum of PMM2-CDG in the Tunisian population. We conducted a retrospective study on patients with genetically confirmed PMM2-CDG, followed between 2005 and 2024. Ten patients from six unrelated Tunisian families were enrolled. All presented with neurological symptoms, including psychomotor delay (10/10), cerebellar ataxia (9/10) and strabismus (9/10). Brain MRI revealed cerebellar atrophy in all patients. Dysmorphic features were common including almond-shaped eyes (9/10), large mouth (6/10), and thin upper lip (6/10). Skeletal anomalies were observed in 9/10 patients. Peripheral neuropathy was confirmed in 6/7 patients. Laboratory analyses revealed elevated transaminases (6/10), hypocholesterolemia (7/10), elevated LDH (7/10), hypoalbuminemia (2/6), and IgA deficiency (3/5). Renal anomalies included hyperechogenicity (2/9) and a duplicated collecting system (1/9). Genetic analysis revealed a homozygous variant NM_000303.3(PMM2): c.395 T > C; p.(Ile132Thr) in all patients. Haplotype analysis of the PMM2 locus showed that all 6 families shared an identical allele. In conclusion, this is the first study to characterize the clinical and genetic profile of PMM2-CDG in the Tunisian population. Despite a shared genotype, patients exhibited moderate neurological phenotypes with inter- and intrafamilial variability. The recurrent homozygous c.395 T > C; p.(Ile132Thr) variant and identical haplotype confirm a founder effect in the Tunisian population.
2026-01-16 | PMM2-CDG and the Role of Liver Transplantation as a Long-Term Solution: A Case Report.
Phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG) is the most common congenital disorder of glycosylation, affecting protein glycosylation across multiple organ systems. Hepatic involvement may range from isolated elevations in liver transaminases to end-stage liver disease. Reported outcomes of liver transplantation as a treatment modality are sparse. We describe one of the first reported cases of liver transplantation in a child with PMM2-CDG and interim post-transplant outcomes. This patient was diagnosed at 4 months of age after presenting with failure to thrive, lipodystrophy, hypotonia, developmental delay, elevated transaminases, hypoalbuminemia, and coagulopathy. He developed cirrhosis and portal hypertension as well as sequelae of poor protein glycosylation. All these included coagulopathy, protein-losing enteropathy, and refractory ascites requiring serial intravenous fresh frozen plasma and furosemide. He ultimately underwent a liver transplant, after which his ascites resolved. Post-transplant, he developed new-onset recurrent pericardial effusions, suspected to be from a viral etiology versus extrahepatic manifestations of PMM2-CDG, and elevated transaminases following transplantation. Liver transplantation may offer clinical benefit in PMM2-CDG with severe hepatic involvement, including resolution of ascites and improved quality of life, due to its potential to restore liver glycosylation function. However, this is only a partial correction as persistent extrahepatic manifestations underscore the need for further research into transplant outcomes and systemic disease progression in CDG.
2026-01-01 | Modeling human PMM2-CDG in medaka to understand systemic effects of hypoglycosylation on development
Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases caused by mutations in the enzymes involved in glycosylation. To date, no conclusive pathogenic mechanism is linked to the disease and there are only limited therapeutic options available. The most common form of CDG is caused by compound heterozygous hypomorphic alleles of the cytosolic enzyme Phosphomannomutase 2 (PMM2), leading to global protein hypoglycosylation and a multiorgan phenotype in patients. Complete loss-of-function mutations in the essential protein are incompatible with life. Patients that survive carry mutations that lead to reduced enzyme activity of PMM2. PMM2 plays a crucial role at the basis of the glycosylation cascade in the endoplasmic reticulum by providing the essential mannose precursor required for the three glycosylation routes N-glycosylation, O- and C-mannosylation. The entire glycosylation machinery is evolutionarily highly conserved which allows generating translational models in other organisms. The small teleost medaka (Oryzias latipes) offers a great advantage as model organism to investigate the early embryogenesis through the extrauterine and transparent developing embryos. To understand acute effects of Pmm2 loss on development and disease progression, I have created translational models that mimic the reduced residual enzyme activity of PMM2-CDG patients. I followed two routes to investigate the role of PMM2 on development: establish a conditional knockdown system for acute Pmm2 interference at the protein level and patient-based genetic models by precision genome editing in medaka. For the conditional knockdown in medaka, I applied an inducible degron system to selectively degrade Pmm2-GFP, mimicking reduced enzyme activity. To generate patient-based pmm2 alleles, I used canonical base editing to generate the p.C139R mutation and a deletion variant. Further, I developed and carefully examined a novel two step one-shot base editing approach termed “inception”. Inception introduces a new binding site for a second base editing event that subsequently leads to the anticipated edit. With inception I created one of the common patient mutations p.F119L. Depending on the generated alleles, different pmm2 variants resulted in varying enzymatic activity in medaka, phenocopied the patient symptoms and caused hypoglycosylation of proteins. Bottom-up proteomics revealed molecular changes already present before the onset of multisystemic phenotypes, affecting particularly mRNA processing and eye development.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles and probability of success in trials forecasts:
Drug Discovery Landscape
4 orphan drug designations for PMM2-CDG.
4 orphan drug designations for PMM2-CDG.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid | small molecules | FDA | 2020-09-21 | — | Applied Therapeutics Inc. |
epalrestat | small molecules | FDA | 2020-03-26 | — | Maggie's Pearl |
Liposomal mannose-1-phosphate | small molecules | EMA | 2018-07-31 | — | Regintel Limited |
liposomal mannose-1-phosphate | small molecules | FDA | 2018-06-04 | — | Glycomine, Inc. |
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