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
148 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:
148 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:
categories:
Small molecules
proteins
2025-05-23 | Establishing an auxin-inducible GFP nanobody-based acute protein knockdown system to mimic hypomorphic mutations during early medaka embryogenesis
Abstract Creating hypomorphic mutations are crucial to study gene function in vivo , especially when null mutations result in (embryonic) lethality. This is especially the case for enzymes involved in glycosylation that, when mutated in human patients, are causing the disease congenital disorders of glycosylation (CDG). To resemble the patient conditions, it would be ideal to acutely modulate the proteins in question to directly interfere with protein levels of such essential enzymes. These methods offer to establish pathogenic enzyme levels resembling net enzyme activity reported from patients suffering from CDG, with Phosphomannomutase 2 - CDG (PMM2-CDG) as the most common form. We established an auxin-inducible acute protein knockdown system for the use in the teleost fish medaka ( Oryzias latipes ) by combining an improved degron (AID2) technology with a mAID-nanobody targeting endogenously GFP-tagged Pmm2 protein. We generated a fishline expressing a functional Pmm2-GFP fusion protein, by single copy integration of GFP into the pmm2 locus. Upon induction, the degron system efficiently reduced Pmm2-GFP levels and enzyme activity, recapitulating the activity level of the hypomorphic mutations associated with PMM2-CDG in patients. This broadly applicable approach enables the investigation of CDG disease mechanisms during early embryonic development through reduction of protein abundance mimicking hypomorphic mutations and thus substantially expands the range of the genetic toolbox. Summary Statement The combination of TIR1F74G and mAID-GFP-nanobody enables efficient acute knockdown of endogenously GFP-tagged proteins in medaka. This approach successfully reduced Pmm2 enzyme activity to pathological levels as seen in PMM2-CDG patients.
2024-10-01 | 8015 Growth Hormone Axis Dysfunction in PMM2-CDG: Exploring the Role of Dynamic Tests for the Management of Short Stature in Two Pediatric Cases
Abstract Disclosure: G. Del Medico: None. E. Procopio: None. L. Ferri: None. A. Barbato: None. A. Morrone: None. S. Stagi: None. PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) and is caused by defective phosphomannomutase2 (PMM2) activity. According to the 2019 guidelines, approximately half of PMM2-CDG patients exhibit short stature and low serum levels of insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGFBP3), and acid-labile subunit (ALS). Despite this, there is no expert consensus on the endocrinological management of this condition. We investigated the growth hormone (GH) axis in two 12-year-old female patients with PMM2-CDG. The first patient was compound heterozygote for the most common PMM2 gene variants in Italy, p.(Leu32Arg) and p.(Arg141His). She presented with short stature (< 2 Standard Deviation Score, SDS) and low serum levels of IGF-1 and IGF-BP3 (< 2.5° for age and sex). Bone age was significantly delayed. Tanner stage was prepubertal. Somatotropic response to GH stimulation testing (Levodopa) was normal. After the IGF-1 generation test with recombinant GH, serum IGF-1 increased by 115%. The second patient was compound heterozygote for the known PMM2 pathogenetic variant p.(Ala108Val) and the novel p.(Thr171Asnfs*11) variant (only case described in literature). She presented short stature (< 2 SDS) with near-to-normal IGF-1 and IGF-BP3 serum levels (2.5° for age and sex). Bone age was slightly delayed. Tanner stage was prepubertal. She also exhibited severe obesity, hypertriglyceridemia, and hepatic steatosis. Her somatotropic response to two GH stimulation tests (Levodopa and Arginine) was deficient, probably because of her significant overweight. IGF-1 serum levels didn’t increase after the IGF-1 generation test. Hypoglycosylation in PMM2-CDG impairs the IGF1 system on multiple levels. It destabilizes the ternary complex formed by IGF-1 and glycoproteins IGFBP3 and ALS, therefore reducing the half-life of circulating IGF-1. Hypoglycosylation also reduces IGF1 production by impairing its precursor proIGF-1Ea and its cellular secretion. As a result, PMM2-CDG patients have GH insensitivity, with normal GH production but low levels of IGF-1. However, there is a lack of information in the literature on the use of dynamic tests and hormonal therapies (GH and rhIGF-1) in CDG. The IGF-1 generation test in our patients showed partial GH sensitivity in the first patient and GH insensitivity in the second patient. These observations suggest variability. Some PMM2-CDG patients may benefit from an extended trial with GH therapy, while for GH-insensitive patients a trial with recombinant IGF-1 might be considered. This is one of the first reports that explores the potential role of dynamic tests in PMM2-CDG. As the biochemical effects of hypoglycosylation on the GH-IGF1 pathway are becoming clearer more clinical research is needed to reach a consensus on the management and treatment of short stature in these patients. Presentation: 6/3/2024
2024-04-01 | Revisiting the immunopathology of congenital disorders of glycosylation: an updated review.
Glycosylation is a critical post-translational modification that plays a pivotal role in several biological processes, such as the immune response. Alterations in glycosylation can modulate the course of various pathologies, such as the case of congenital disorders of glycosylation (CDG), a group of more than 160 rare and complex genetic diseases. Although the link between glycosylation and immune dysfunction has already been recognized, the immune involvement in most CDG remains largely unexplored and poorly understood. In this study, we provide an update on the immune dysfunction and clinical manifestations of the 12 CDG with major immune involvement, organized into 6 categories of inborn errors of immunity according to the International Union of Immunological Societies (IUIS). The immune involvement in phosphomannomutase 2 (PMM2)-CDG - the most frequent CDG - was comprehensively reviewed, highlighting a higher prevalence of immune issues during infancy and childhood and in R141H-bearing genotypes. Finally, using PMM2-CDG as a model, we point to links between abnormal glycosylation patterns in host cells and possibly favored interactions with microorganisms that may explain the higher susceptibility to infection. Further characterizing immunopathology and unusual host-pathogen adhesion in CDG can not only improve immunological standards of care but also pave the way for innovative preventive measures and targeted glycan-based therapies that may improve quality of life for people living with CDG.
2023-07-03 | Complex metabolic disharmony in PMM2-CDG paves the way to new therapeutic approaches.
PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids, lysosomal proteins, organic acids and lipids were measured, which all revealed significant abnormalities. There was an increased expression of acylcarnitines and amino acids associated with increased amounts of calnexin, calreticulin and protein-disulfid-isomerase in combination with intensified amounts of ubiquitinylated proteins. Lysosomal enzyme activities were widely decreased as well as citrate and pyruvate levels indicating mitochondrial dysfunction. Main lipid classes such as phosphatidylethanolamine, cholesterol or alkyl-phosphatidylcholine, as well as minor lipid species like hexosylceramide, lysophosphatidylcholines or phosphatidylglycerol, were abnormal. Biotinidase and catalase activities were severely reduced. In this study we discuss the impact of metabolite abnormalities on the phenotype of PMM2-CDG. In addition, based on our data we propose new and easy-to-implement therapeutic approaches for PMM2-CDG patients.
2022-10-20 | Evolutionary rescue of phosphomannomutase deficiency in yeast models of human disease.
The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene PMM2, which affect protein N-linked glycosylation. The yeast gene SEC53 encodes a homolog of human PMM2. We evolved 384 populations of yeast harboring one of two human-disease-associated alleles, sec53-V238M and sec53-F126L, or wild-type SEC53. We find that after 1000 generations, most populations compensate for the slow-growth phenotype associated with the sec53 human-disease-associated alleles. Through whole-genome sequencing we identify compensatory mutations, including known SEC53 genetic interactors. We observe an enrichment of compensatory mutations in other genes whose human homologs are associated with Type 1 CDG, including PGM1, which encodes the minor isoform of phosphoglucomutase in yeast. By genetic reconstruction, we show that evolved pgm1 mutations are dominant and allele-specific genetic interactors that restore both protein glycosylation and growth of yeast harboring the sec53-V238M allele. Finally, we characterize the enzymatic activity of purified Pgm1 mutant proteins. We find that reduction, but not elimination, of Pgm1 activity best compensates for the deleterious phenotypes associated with the sec53-V238M allele. Broadly, our results demonstrate the power of experimental evolution as a tool for identifying genes and pathways that compensate for human-disease-associated alleles.
gene therapies
2026-07-27 | Congenital Disorder of Glycosylation Type Ia (Jaeken Syndrome): A Case Report
Background . Congenital disorder of glycosylation type Ia (Jaeken syndrome; congenital disorder of glycosylation, type Ia; CDG-Ia) is a hereditary progressive disorder with a pronounced neurodegenerative component, caused by pathogenic variants in the PMM2 gene (encoding the enzyme phosphomannomutase-2). CDG-Ia accounts for the majority of registered patients with congenital disorders of glycosylation (62% in 2018). At least 1,000 patients with CDG caused by PMM2 gene mutations are known, but due to diagnostic difficulties, the true number of individuals with this condition is undoubtedly much higher. Case Report . We present a case report of CDG-Ia in a child with progressive ataxia, nystagmus, and delayed psycho-speech and motor development. The patient was a female infant, born from the third pregnancy, which was complicated by acute enteritis at 15 weeks of gestation and an acute respiratory viral infection at 20 weeks of gestation. Delivery was at term (42 weeks) and was the second childbirth. The child was born into a family with no history of hereditary disorders; the parents were 37 and 38 years old at the time of the girl’s birth. The disease manifested from birth with reduced sucking reflex, breast refusal, and slow weight gain. At 1.5 months of age, horizontal nystagmus was added to these symptoms. The diagnosis was established based on molecular genetic testing of the proband using next-generation sequencing to rule out hereditary ataxias, as well as transferrin isoelectric focusing (revealing an abnormal transferrin spectrum: abnormal diand asialotransferrins — isoforms S2 and S0), and magnetic resonance imaging of the brain (showing progressive cerebellar atrophy at 11 months of age). Conclusion. We describe a case report of CDG-Ia in a child from a family in which both parents are carriers of mutant alleles and have a healthy child. Despite comprehensive patient management, progressive disease course was observed; the girl has severe psychomotor retardation and clinical signs of multisystem involvement of internal organs. Arresting disease progression is not feasible due to the underlying genetic defect in the synthesis of mannose and glycoproteins, which are essential components of most metabolic pathways in the body.
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.
2026-01-01 | 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.
2025-12-23 | Clinical and genetic characterization of congenital disorders of glycosylation in 20 Chinese patients
BACKGROUND: Congenital disorders of glycosylation (CDG) are a complex and heterogeneous family of rare metabolic diseases that affect protein and lipid glycosylation and glycosylphosphatidylinositol synthesis. These disorders can affect multiple organs, leading to a broad spectrum of symptoms that vary among different CDG subtypes and between individuals with same type of CDG. This study aimed to investigate the genetic variants, molecular etiologies, and clinical features of 20 Chinese patients diagnosed with CDG. RESULTS: Using whole-exome sequencing (WES), functional prediction tools, Sanger sequencing, and segregation analysis, we identified variants in several genes: ALG2 (3 patients), DPM2 (3 patients), PMM2 (3 patients), and ALG13 (2 patients). Additionally, variants in COG5, COG6, MOGS, DPM3, ALG1, ALG3, ALG11, SSR4 and SLC35A2 each were observed in single case. In total, 28 distinct variants were identified, 11 of which were previously unreported. Genotype-phenotype correlations revealed notable findings: variants in the N-terminus of ALG2 before the intramembrane domain were associated with congenital myasthenic syndromes (CMS), whereas those in the C-terminus caused ALG2-CDG; DPM2-CDG patients with variants in transmembrane region 1 exhibited more severe phenotypes; male patients with hemizygous variants in SLC35A2 demonstrated milder phenotypes compared to those with mosaic variants. CONCLUSIONS: This findings expand the spectrum of known clinical presentations and genetic variants in CDG, and establish possible genotype-phenotype correlations of several pathogenic genes, emphasizing the need for functional studies to unravel the underlying mechanisms.
2025-12-15 | Identification of Two Siblings with PMM2-Congenital Disorder of Glycosylation Using Exome Sequencing in South East of Iran: Clinical and Genetic Findings
Background: Congenital disorders of glycosylation (CDG) encompass a broad spectrum of rare inborn errors of metabolism (IEMs), resulting in defective glycosylation of various proteins and/or lipids. PMM2-CDG is the most prevalent subtype of CDG, characterized by gene mutations leading to deficiency of the phosphomannomutase 2 (PMM2) enzyme. This research identified two Iranian patients from a consanguineous family with multiple organ dysfunctions, diagnosed with PMM2-CDG due to a pathogenic variant in the PMM2 gene. The study underscores the importance of identifying specific variants in different ethnic groups for effective genetic counseling for this disorder. Methods: The study utilized exome sequencing (ES) to identify pathogenic variants. Verification of the potential variant in affected siblings, along with segregation analysis involving the parents, affected individuals, and healthy siblings of the family, was performed using Sanger sequencing. Interpretation of the variant was informed by multiple in silico analysis tools, as well as by adhering to the guidelines set forth by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). Results: In the genomic investigations of the two brothers with intellectual disability (ID) and progressive movement disability, the NM_000303.3:c.647A > T (NP_000294.1:p.Asn216Ile) homozygous variant in the PMM2 gene was identified. The variant was confirmed in the affected and other family members by segregation analysis. Multiple in silico tools supported the pathogenic classification of the identified variant. Conclusions: The findings provide broader insight into variants within the PMM2 gene and offer a thorough characterization of the phenotype related to this specific variant. The data have important applications for genetic diagnosis and counseling in relevant clinical contexts, as well as for identifying common gene variants associated with various ethnic groups. Additionally, this information could serve as a valuable resource in guiding therapeutic interventions.
small molecules
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).
2025-10-23 | Treatment of Single Patient With PMM2‐Congenital Disorder of Glycosylation With Govorestat (AT‐007), an Aldose Reductase Inhibitor
Aldose reductase inhibitors (ARI) have been identified as a potential treatment for phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG), a serious condition for which no treatments are approved. We treated a single patient for 36 months 30 months of age at enrollment, under a single-patient investigational new drug expanded access request, with govorestat (AT-007), a novel, highly selective, once daily, brain penetrant ARI at a starting dose of 1 mg/kg oral suspension, which was escalated to 30 mg/kg. The primary endpoint was safety. Secondary assessments included liver transaminases, factor XI, antithrombin III, and whole blood and urine sorbitol. Clinical outcomes were also assessed, including Nijmegen Pediatric CDG Rating Scale (NPCRS), Bayley Scales of Infant Development, and Vineland Adaptive Behavioral Scale. Govorestat was well tolerated; no adverse effects were noted. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels improved from a pre-treatment 12-month average of 205 and 268 U/L to 63 and 68 U/L, respectively, averaged over 36 months of govorestat treatment at 30 mg/kg. Antithrombin III and factor XI fluctuated with illness throughout the study period but overall increased by 60%-100%, approaching the normal range (> 83% activity) at the 5 mg/kg dose. Whole blood sorbitol decreased in a dose-dependent fashion, normalizing at the 30 mg/kg dose. The NPCRS improved by 9 points (46%) over the course of treatment. In conclusion, our patient tolerated govorestat without safety concerns. Improvements in liver transaminases, clotting factors, and whole blood sorbitol were observed along with improvements in clinical measures. These findings support further study of govorestat as a potential treatment for PMM2-CDG.
2025-10-15 | Treatment of Single Patient With PMM2-Congenital Disorder of Glycosylation With Govorestat (AT-007), an Aldose Reductase Inhibitor.
Aldose reductase inhibitors (ARI) have been identified as a potential treatment for phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG), a serious condition for which no treatments are approved. We treated a single patient for 36 months 30 months of age at enrollment, under a single-patient investigational new drug expanded access request, with govorestat (AT-007), a novel, highly selective, once daily, brain penetrant ARI at a starting dose of 1 mg/kg oral suspension, which was escalated to 30 mg/kg. The primary endpoint was safety. Secondary assessments included liver transaminases, factor XI, antithrombin III, and whole blood and urine sorbitol. Clinical outcomes were also assessed, including Nijmegen Pediatric CDG Rating Scale (NPCRS), Bayley Scales of Infant Development, and Vineland Adaptive Behavioral Scale. Govorestat was well tolerated; no adverse effects were noted. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels improved from a pre-treatment 12-month average of 205 and 268 U/L to 63 and 68 U/L, respectively, averaged over 36 months of govorestat treatment at 30 mg/kg. Antithrombin III and factor XI fluctuated with illness throughout the study period but overall increased by 60%-100%, approaching the normal range (> 83% activity) at the 5 mg/kg dose. Whole blood sorbitol decreased in a dose-dependent fashion, normalizing at the 30 mg/kg dose. The NPCRS improved by 9 points (46%) over the course of treatment. In conclusion, our patient tolerated govorestat without safety concerns. Improvements in liver transaminases, clotting factors, and whole blood sorbitol were observed along with improvements in clinical measures. These findings support further study of govorestat as a potential treatment for PMM2-CDG.
2025-10-07 | Exploring Secondary Biotinidase Deficiency and Biotin Supplementation in PMM2-CDG.
The congenital disorders of glycosylation (CDG) encompass >190 multiorgan disorders with predominantly neurodevelopmental phenotypes with no causative treatment available. The glycoprotein biotinidase (BTD) provides biotin, an essential cofactor for carboxylases in ubiquitous metabolic pathways. Individuals with (partial) BTD deficiency (BTDD) and CDG patients show overlapping phenotypes like movement disorders, seizures, and neurodevelopmental issues. Biotin is a water-soluble, inexpensive, and safe food supplement. Patients with primary BTDD respond well to oral biotin supplement. We here explore secondary BTDD and the effect of biotin supplementation in PMM2-CDG in an initial open-label study.BTD activity in dried blood spots from 29 individuals with PMM2-CDG indicated a mean reduction to 27% (range: 23.0-40.5%) at group level. Patients (mean: 19.6 ± 11.9 years) were supplemented with 10 mg biotin daily for 12 months. The parents/caretaker reported positive responses in 62 to 69% of patients across seven (performance, social, at home, self-control, self-care, leisure, health) of the nine categories covered by the Adaptive Behavior Assessment System-II (ABAS-II) questionnaires. The reported positive effect of biotin supplementation differed between age groups, ranging from 54% (16-43 years) via 62% (2-5 years) to 80% (6-13 years). Its effect was reported to be the highest in the moderate to severely affected patient subgroups, with significant improvements in home functioning, health, performance, leisure, self-control. No adverse effects were reported.Given the absence of other treatments, the supportive effect of Biotin in PMM2-CDG deserves further exploration.
2025-10-01 | SUN-616 Phosphomannomutase 2 (PMM2)-Congenital Disorder of Glycosylation in a Patient with Dandy Walker Malformation
Abstract Disclosure: M. Kazim: None. S.S. Krishnasamy: None. Background: (PMM2)-congenital disorder of glycosylation (CDG) is a disorder of protein N-glycosylation characterized by deficiency/dysfunction of PMM2. We present a case of a patient with Dandy Walker Malformation (DWM) presenting with severe persistent hypoglycemia. Clinical Case: We were consulted on 24 y old African American female known case of DWM, congenital bilateral hearing loss, epilepsy, cerebral palsy, primary ovarian failure and, venous thromboembolism (VTE) for evaluation of persistent hypoglycemia. At birth she was in the NICU for hypoglycemia however since then she did not have any documented symptomatic hypoglycemia. Patient now presented with hypoglycemic symptoms after recent hospitalization for VTE and renal infarct. Labs showed ACTH 7 pg/mL, AM cortisol 10.2 mcg/dL, glucose 50mg/dl, C-peptide of 1.97 ng/ml, proinsulin 47 pmol/L, insulin 18.1 uIU/ml, Prolactin 10.4 ng/ml, TSH 1.71 mIU/L, Free T4 1.1 ng/dL, IGF-1 343 ng/mL, FSH 160 mIU/mL, LH 63.2 mIU/mL. CT abdomen and pelvis showed no pathology of the pancreas. Patient was hospitalized with severe hypoglycemia not responding to D10 infusion. Given hyper insulinemic hypoglycemia resistant to intravenous dextrose we initiated diazoxide 3 mg/kg q8h. she was also started on glucocorticoids for suspicion of autoimmune etiology of hypoglycemia. She responded quite well with improving blood sugars. She was referred to genetics given no clear cause of hypoglycemia established. Carbohydrate deficient transferrin test showed increased Mono-Oligo/Di-Oligo ratio of 0.32 (normal <0.06) and A-Oligo/Di-Oligo Ratio of 0.123 (normal <0.011). Patient is now on a stable regimen with diazoxide 100mg by mouth every 6 hours and high protein/complex carbohydrate diet with improvement of hypoglycemia. Conclusion: CDG are a wide spectrum of disorders associated with dysfunction of multiple organs particularly the brain and endocrine system. Cerebellar atrophy has been reported in 95.4% of cases with PMM2- CGD with the most common cerebellar symptom in patients being ataxia (1). To our knowledge only one other case has been published with PMM2- CDG and Dandy Walker Malformation (DWM). Due to paucity of cases involving CDG and DWM it is unclear if DWM is a separate entity in these patients or caused by CDG itself. CDG should be considered as a differential in patients with DWM presenting with hypoglycemia even in later aspect of life. Reference: (1)Altassan R, Péanne R, Jaeken J, et al. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up [published correction appears in J Inherit Metab Dis. 2019 May;42(3):577. doi: 10.1002/jimd.12082]. J Inherit Metab Dis. 2019;42(1):5-28. doi:10.1002/jimd.12024 Presentation: Sunday, July 13, 2025
cell therapies
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.
2025-05-08 | Targeted metabolomic evaluation of peripheral blood mononucleated cells from patients with PMM2-CDG.
Phosphomannomutase-2 (PMM2) deficiency represents the most common congenital disorder of glycosylation (CDG). Currently, little is known about cell metabolic alterations occurring in these patients. Here, we quantified compounds connected to protein glycosylation (GDP-mannose, UDP-derivatives), energy metabolism (high-energy phosphates, nicotinic coenzymes, oxypurines), oxidative/nitrosative stress (GSH, nitrite, nitrate) and free amino acids in extracts of peripheral blood mononucleated cells (PBMCs), of seven PMM2-CDG patients and ten control healthy donors. Besides marked GDP-mannose decrease, PBMCs of PMM2-CDG patients had higher UDP-glucose (UDP-Glc), UDP-galactose (UDP-Gal) and UDP-Glucuronic levels, lower ATP, GTP and UTP levels, abnormal ATP/ADP, ATP/AMP and NAD+/NADH ratios, increased xanthine, uric acid and nitrite + nitrate levels, and decreased GSH and free amino acids concentrations. These results suggest a new, conceivable metabolic route leading to the increase of specific UDP-derivatives (UDP-Glc, UDP-Gal and UDP-Glucuronic), also potentially explaining the glycogen abnormalities recently found in PMM2-CDG patients. Altogether, this study highlighted various metabolic changes caused by PMM2 deficiency, illustrating the widespread effects of PMM2 mutations (beyond N-glycan biosynthesis) that may significantly vary depending on the cell line considered. Using PBMCs, as a cellular model of lower invasiveness than skin fibroblast, may advantage cell metabolism studies to investigate new therapies specifically targeted to PMM2 deficiency.
2023-04-25 | Liver transplantation recovers hepatic N-glycosylation with persistent IgG glycosylation abnormalities: Three-year follow-up in a patient with phosphomannomutase-2-congenital disorder of glycosylation.
Phosphomannomutase-2-congenital disorder of glycosylation (PMM2-CDG) is the most common CDG and presents with highly variable features ranging from isolated neurologic involvement to severe multi-organ dysfunction. Liver abnormalities occur in in almost all patients and frequently include hepatomegaly and elevated aminotransferases, although only a minority of patients develop progressive hepatic fibrosis and liver failure. No curative therapies are currently available for PMM2-CDG, although investigation into several novel therapies is ongoing. We report the first successful liver transplantation in a 4-year-old patient with PMM2-CDG. Over a 3-year follow-up period, she demonstrated improved growth and neurocognitive development and complete normalization of liver enzymes, coagulation parameters, and carbohydrate-deficient transferrin profile, but persistently abnormal IgG glycosylation and recurrent upper airway infections that did not require hospitalization. Liver transplant should be considered as a treatment option for PMM2-CDG patients with end-stage liver disease, however these patients may be at increased risk for recurrent bacterial infections post-transplant.
2022-05-06 | Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation
Congenital disorders of glycosylation (CDG) are inherited metabolic diseases characterized by mutations in enzymes involved in different steps of protein glycosylation, leading to aberrant synthesis, attachment or processing of glycans. Recently, immunological dysfunctions in several CDG types have been increasingly documented. Despite these observations, detailed studies on immune cell dysfunction in PMM2-CDG and other CDG types are still scarce. Studying PMM2-CDG patient immune cells is challenging due to limited availability of patient material, which is a result of the low incidence of the disease and the often young age of the subjects. Dedicated immune cell models, mimicking PMM2-CDG, could circumvent many of these problems and facilitate research into the mechanisms of immune dysfunction. Here we provide initial observations about the immunophenotype and the phagocytic function of primary PMM2-CDG monocytes. Furthermore, we assessed the suitability of two different glycosylation-impaired human monocyte models: tunicamycin-treated THP-1 monocytes and PMM2 knockdown THP-1 monocytes induced by shRNAs. We found no significant differences in primary monocyte subpopulations of PMM2-CDG patients as compared to healthy individuals but we did observe anomalous surface glycosylation patterns in PMM2-CDG patient monocytes as determined using fluorescent lectin binding. We also looked at the capacity of monocytes to bind and internalize fungal particles and found a slightly increased uptake of C. albicans by PMM2-CDG monocytes as compared to healthy monocytes. Tunicamycin-treated THP-1 monocytes showed a highly decreased uptake of fungal particles, accompanied by a strong decrease in glycosylation levels and a high induction of ER stress. In contrast and despite a drastic reduction of the PMM2 enzyme activity, PMM2 knockdown THP-1 monocytes showed no changes in global surface glycosylation levels, levels of fungal particle uptake similar to control monocytes, and no ER stress induction. Collectively, these initial observations suggest that the absence of ER stress in PMM2 knockdown THP-1 cells make this model superior over tunicamycin-treated THP-1 cells and more comparable to primary PMM2-CDG monocytes. Further development and exploitation of CDG monocyte models will be essential for future in-depth studies to ultimately unravel the mechanisms of immune dysfunction in CDG.
other
2025-10-06 | Immunopathology in PMM2-CDG: Defective glycosylation impact in the TNFα -TNFR1 signalling pathway.
Glycosylation is a post-translational modification that plays a crucial role in immune system activity. Phosphomannomutase 2-Congenital Disorder of Glycosylation (PMM2-CDG) is a rare genetic disease affecting glycosylation with a multi-systemic impact. PMM2-CDG patients commonly show immune disfunction and elevated pro-inflammatory cytokine levels that may link to other symptoms. However, the underlying immune mechanisms remain unclear. Given Tumour Necrosis Factor (TNF)'s key role in inflammation, this study proposes that defective glycosylation of its receptors disrupts intracellular signalling, leading to changes in the immune response of PMM2-CDG patients. To address this, we applied an integrative approach, combining transcriptomics, glycomics, and immune-related assays to investigate the impact of TNF-a stimulation via TNF receptor 1 (TNFR1) in a cohort of PMM2-CDG patients' skin fibroblasts. Our results reveal a multifaceted disruption of TNF-a signalling in PMM2-CDG fibroblasts. We observed structural abnormalities in TNFR1, including altered receptor shedding. PMM2-CDG cells also showed an altered N-glycosylation profile, affecting particularly, high mannose N-glycans. At transcriptional level, PMM2-CDG cells, especially those bearing the R141H heterozygous variant, exhibited a distinct gene expression profile, after stimulation, characterized by dysregulation of immune and signalling pathways. Functionally, these molecular alterations translated into a diminished secretion of key inflammation and infection mediators, such as interleukin-6 (IL-6) and C-C Motif chemokine ligand 5 (CCL5) upon TNF-a stimulation. Similarly, essential signalling kinases including extracellular-signal-regulated kinase (ERK) 1/2, p38 and c-Jun N- terminal kinase (JNK) 2 showed reduced expression in PMM2-CDG cells, and their expression did not alter following TNF-a stimulation, unlike control cells. Our findings point to TNFR1 signalling dysregulation as a key contributor to immune dysfunction in PMM2-CDG. Importantly, our study identifies TNFR1 as a promising therapeutic target, suggesting that strategies aimed at modulating TNFR1 activity or restoring glycosylation homeostasis could provide new approaches for treatment development. This work advances our understanding of PMM2 -CDG immunopathology and opens opportunities for targeted therapeutics.
2023-06-02 | A liposomal carbohydrate vaccine, adjuvanted with an NKT cell agonist, induces rapid and enhanced immune responses and antibody class switching
Congenital disorders of glycosylation (CDGs) are genetic diseases caused by gene defects in glycan biosynthesis pathways, and there is an increasing number of patients diagnosed with CDGs. Because CDGs show many different clinical symptoms, their accurate clinical diagnosis is challenging. Recently, we have shown that liposome nanoparticles bearing the ALG1-CDG and PMM2-CDG biomarkers (a tetrasaccharide: Neu5Ac-α2,6-Gal-β1,4-GlcNAc-β1,4-GlcNAc) stimulate a moderate immune response, while the generated antibodies show relatively weak affinity maturation. Thus, mature antibodies with class switching to IgG are desired to develop high-affinity antibodies that may be applied in medical applications.In the present study, a liposome-based vaccine platform carrying a chemoenzymatic synthesized phytanyl-linked tetrasaccharide biomarker was optimized. The liposome nanoparticles were constructed by dioleoylphosphatidylcholine (DOPC) to improve the stability and immunogenicity of the vaccine, and adjuvanted with the NKT cell agonist PBS57 to generate high level of IgG antibodies. The results indicated that the reformulated liposomal vaccine stimulated a stronger immune response, and PBS57 successfully induce an antibody class switch to IgG. Further analyses of IgG antibodies elicited by liposome vaccines suggested their specific binding to tetrasaccharide biomarkers, which were mainly IgG2b isotypes.Immunization with a liposome vaccine carrying a carbohydrate antigen and PBS57 stimulates high titers of CDG biomarker-specific IgG antibodies, thereby showing great potential as a platform to develop rapid diagnostic methods for ALG1-CDG and PMM2-CDG.
2019-08-07 | Hypolipidaemia among patients with PMM2-CDG is associated with low circulating PCSK9 levels: a case report followed by observational and experimental studies
Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel therapeutics for reducing low-density lipoprotein cholesterol (LDLc). While serious side-effects have not been observed in short-term clinical trials, there remain concerns that long-term PCSK9 inhibition may cause neurocognitive side-effects. Methods and results An adult male with childhood-onset global developmental delay, cerebellar atrophy and severe hypolipidaemia underwent extensive biochemical and genetic investigations. Initial testing revealed low circulating PCSK9 levels and a common loss-of-function PCSK9 polymorphism, but these findings did not fully account for severe hypolipidaemia. Whole-exome sequencing was subsequently performed and identified two pathogenic phosphomannose mutase 2 (PMM2) variants (p.Arg141His and p.Pro69Ser) known to cause PMM2-associated congenital disorder of glycosylation (PMM2-CDG). A diagnosis of PMM2-CDG was consistent with the proband’s neurological symptoms and severe hypolipidaemia. Given that PMM2-CDG is characterised by defective protein N-glycosylation and that PCSK9 is a negative regulator of LDLc, we postulated that loss of PCSK9 N-glycosylation mediates hypolipidaemia among patients with PMM2-CDG. First, in an independent cohort of patients with PMM2-CDG (N=8), we verified that circulating PCSK9 levels were significantly lower in patients than controls (p=0.0006). Second, we conducted in vitro experiments in hepatocyte-derived cells to evaluate the effects of PCSK9 N-glycosylation loss on LDL receptor (LDLR) activity. Experimental results suggest that defective PCSK9 N-glycosylation reduces the ability of circulating PCSK9 to degrade LDLR. Conclusion Life-long exposure to genetically lower PCSK9 per se is unlikely to cause neurocognitive impairment. Both observational and experimental findings suggest that hypolipidaemia in PMM2-CDG may be partially mediated by loss of PCSK9 N-glycosylation and/or its regulators.
2006-07-06 | Recurrent infections and immunological dysfunction in congenital disorder of glycosylation Ia (CDG Ia)
Summary Congenital disorder of glycosylation Ia is the most common defect of glycosylation and is due to mutations in phosphomannomutase 2. This leads to aberrant N‐linked oligosaccharides. The phenotype of CDG Ia reflects the essential nature of glycosylation and patients typically present with multiple organs affected, with hypotonia, developmental delay, inverted nipples and abnormal fat pads. Later features include retinitis pigmentosa, stroke, cerebellar atrophy and malabsorption. Approximately 20% of patients die in the first year of life and infection is the most common cause of death. Immunological function has not previously been investigated in these patients and the critical role of oligosaccharides on adhesion molecules suggested that haematopoietic cell migration and communication could be disrupted by mutations in phosphomannomutase 2. We characterized the clinical features, performed standard immunological evaluations, and performed specific analyses of neutrophil adhesion molecules on two patients to address this question. Patient neutrophils had diminished chemotaxis but expressed comparable levels of adhesion molecules and rolled on artificial endothelium equivalently to control neutrophils. The most significant feature of the patients’ immunological function was poor vaccine responses. These two affected patients were begun on intravenous immunoglobulin with some improvement in their infections.
proteins
2025-05-23 | Establishing an auxin-inducible GFP nanobody-based acute protein knockdown system to mimic hypomorphic mutations during early medaka embryogenesis
Abstract Creating hypomorphic mutations are crucial to study gene function in vivo , especially when null mutations result in (embryonic) lethality. This is especially the case for enzymes involved in glycosylation that, when mutated in human patients, are causing the disease congenital disorders of glycosylation (CDG). To resemble the patient conditions, it would be ideal to acutely modulate the proteins in question to directly interfere with protein levels of such essential enzymes. These methods offer to establish pathogenic enzyme levels resembling net enzyme activity reported from patients suffering from CDG, with Phosphomannomutase 2 - CDG (PMM2-CDG) as the most common form. We established an auxin-inducible acute protein knockdown system for the use in the teleost fish medaka ( Oryzias latipes ) by combining an improved degron (AID2) technology with a mAID-nanobody targeting endogenously GFP-tagged Pmm2 protein. We generated a fishline expressing a functional Pmm2-GFP fusion protein, by single copy integration of GFP into the pmm2 locus. Upon induction, the degron system efficiently reduced Pmm2-GFP levels and enzyme activity, recapitulating the activity level of the hypomorphic mutations associated with PMM2-CDG in patients. This broadly applicable approach enables the investigation of CDG disease mechanisms during early embryonic development through reduction of protein abundance mimicking hypomorphic mutations and thus substantially expands the range of the genetic toolbox. Summary Statement The combination of TIR1F74G and mAID-GFP-nanobody enables efficient acute knockdown of endogenously GFP-tagged proteins in medaka. This approach successfully reduced Pmm2 enzyme activity to pathological levels as seen in PMM2-CDG patients.
2024-10-01 | 8015 Growth Hormone Axis Dysfunction in PMM2-CDG: Exploring the Role of Dynamic Tests for the Management of Short Stature in Two Pediatric Cases
Abstract Disclosure: G. Del Medico: None. E. Procopio: None. L. Ferri: None. A. Barbato: None. A. Morrone: None. S. Stagi: None. PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) and is caused by defective phosphomannomutase2 (PMM2) activity. According to the 2019 guidelines, approximately half of PMM2-CDG patients exhibit short stature and low serum levels of insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGFBP3), and acid-labile subunit (ALS). Despite this, there is no expert consensus on the endocrinological management of this condition. We investigated the growth hormone (GH) axis in two 12-year-old female patients with PMM2-CDG. The first patient was compound heterozygote for the most common PMM2 gene variants in Italy, p.(Leu32Arg) and p.(Arg141His). She presented with short stature (< 2 Standard Deviation Score, SDS) and low serum levels of IGF-1 and IGF-BP3 (< 2.5° for age and sex). Bone age was significantly delayed. Tanner stage was prepubertal. Somatotropic response to GH stimulation testing (Levodopa) was normal. After the IGF-1 generation test with recombinant GH, serum IGF-1 increased by 115%. The second patient was compound heterozygote for the known PMM2 pathogenetic variant p.(Ala108Val) and the novel p.(Thr171Asnfs*11) variant (only case described in literature). She presented short stature (< 2 SDS) with near-to-normal IGF-1 and IGF-BP3 serum levels (2.5° for age and sex). Bone age was slightly delayed. Tanner stage was prepubertal. She also exhibited severe obesity, hypertriglyceridemia, and hepatic steatosis. Her somatotropic response to two GH stimulation tests (Levodopa and Arginine) was deficient, probably because of her significant overweight. IGF-1 serum levels didn’t increase after the IGF-1 generation test. Hypoglycosylation in PMM2-CDG impairs the IGF1 system on multiple levels. It destabilizes the ternary complex formed by IGF-1 and glycoproteins IGFBP3 and ALS, therefore reducing the half-life of circulating IGF-1. Hypoglycosylation also reduces IGF1 production by impairing its precursor proIGF-1Ea and its cellular secretion. As a result, PMM2-CDG patients have GH insensitivity, with normal GH production but low levels of IGF-1. However, there is a lack of information in the literature on the use of dynamic tests and hormonal therapies (GH and rhIGF-1) in CDG. The IGF-1 generation test in our patients showed partial GH sensitivity in the first patient and GH insensitivity in the second patient. These observations suggest variability. Some PMM2-CDG patients may benefit from an extended trial with GH therapy, while for GH-insensitive patients a trial with recombinant IGF-1 might be considered. This is one of the first reports that explores the potential role of dynamic tests in PMM2-CDG. As the biochemical effects of hypoglycosylation on the GH-IGF1 pathway are becoming clearer more clinical research is needed to reach a consensus on the management and treatment of short stature in these patients. Presentation: 6/3/2024
2024-04-01 | Revisiting the immunopathology of congenital disorders of glycosylation: an updated review.
Glycosylation is a critical post-translational modification that plays a pivotal role in several biological processes, such as the immune response. Alterations in glycosylation can modulate the course of various pathologies, such as the case of congenital disorders of glycosylation (CDG), a group of more than 160 rare and complex genetic diseases. Although the link between glycosylation and immune dysfunction has already been recognized, the immune involvement in most CDG remains largely unexplored and poorly understood. In this study, we provide an update on the immune dysfunction and clinical manifestations of the 12 CDG with major immune involvement, organized into 6 categories of inborn errors of immunity according to the International Union of Immunological Societies (IUIS). The immune involvement in phosphomannomutase 2 (PMM2)-CDG - the most frequent CDG - was comprehensively reviewed, highlighting a higher prevalence of immune issues during infancy and childhood and in R141H-bearing genotypes. Finally, using PMM2-CDG as a model, we point to links between abnormal glycosylation patterns in host cells and possibly favored interactions with microorganisms that may explain the higher susceptibility to infection. Further characterizing immunopathology and unusual host-pathogen adhesion in CDG can not only improve immunological standards of care but also pave the way for innovative preventive measures and targeted glycan-based therapies that may improve quality of life for people living with CDG.
2023-07-03 | Complex metabolic disharmony in PMM2-CDG paves the way to new therapeutic approaches.
PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids, lysosomal proteins, organic acids and lipids were measured, which all revealed significant abnormalities. There was an increased expression of acylcarnitines and amino acids associated with increased amounts of calnexin, calreticulin and protein-disulfid-isomerase in combination with intensified amounts of ubiquitinylated proteins. Lysosomal enzyme activities were widely decreased as well as citrate and pyruvate levels indicating mitochondrial dysfunction. Main lipid classes such as phosphatidylethanolamine, cholesterol or alkyl-phosphatidylcholine, as well as minor lipid species like hexosylceramide, lysophosphatidylcholines or phosphatidylglycerol, were abnormal. Biotinidase and catalase activities were severely reduced. In this study we discuss the impact of metabolite abnormalities on the phenotype of PMM2-CDG. In addition, based on our data we propose new and easy-to-implement therapeutic approaches for PMM2-CDG patients.
2022-10-20 | Evolutionary rescue of phosphomannomutase deficiency in yeast models of human disease.
The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene PMM2, which affect protein N-linked glycosylation. The yeast gene SEC53 encodes a homolog of human PMM2. We evolved 384 populations of yeast harboring one of two human-disease-associated alleles, sec53-V238M and sec53-F126L, or wild-type SEC53. We find that after 1000 generations, most populations compensate for the slow-growth phenotype associated with the sec53 human-disease-associated alleles. Through whole-genome sequencing we identify compensatory mutations, including known SEC53 genetic interactors. We observe an enrichment of compensatory mutations in other genes whose human homologs are associated with Type 1 CDG, including PGM1, which encodes the minor isoform of phosphoglucomutase in yeast. By genetic reconstruction, we show that evolved pgm1 mutations are dominant and allele-specific genetic interactors that restore both protein glycosylation and growth of yeast harboring the sec53-V238M allele. Finally, we characterize the enzymatic activity of purified Pgm1 mutant proteins. We find that reduction, but not elimination, of Pgm1 activity best compensates for the deleterious phenotypes associated with the sec53-V238M allele. Broadly, our results demonstrate the power of experimental evolution as a tool for identifying genes and pathways that compensate for human-disease-associated alleles.
gene therapies
2026-07-27 | Congenital Disorder of Glycosylation Type Ia (Jaeken Syndrome): A Case Report
Background . Congenital disorder of glycosylation type Ia (Jaeken syndrome; congenital disorder of glycosylation, type Ia; CDG-Ia) is a hereditary progressive disorder with a pronounced neurodegenerative component, caused by pathogenic variants in the PMM2 gene (encoding the enzyme phosphomannomutase-2). CDG-Ia accounts for the majority of registered patients with congenital disorders of glycosylation (62% in 2018). At least 1,000 patients with CDG caused by PMM2 gene mutations are known, but due to diagnostic difficulties, the true number of individuals with this condition is undoubtedly much higher. Case Report . We present a case report of CDG-Ia in a child with progressive ataxia, nystagmus, and delayed psycho-speech and motor development. The patient was a female infant, born from the third pregnancy, which was complicated by acute enteritis at 15 weeks of gestation and an acute respiratory viral infection at 20 weeks of gestation. Delivery was at term (42 weeks) and was the second childbirth. The child was born into a family with no history of hereditary disorders; the parents were 37 and 38 years old at the time of the girl’s birth. The disease manifested from birth with reduced sucking reflex, breast refusal, and slow weight gain. At 1.5 months of age, horizontal nystagmus was added to these symptoms. The diagnosis was established based on molecular genetic testing of the proband using next-generation sequencing to rule out hereditary ataxias, as well as transferrin isoelectric focusing (revealing an abnormal transferrin spectrum: abnormal diand asialotransferrins — isoforms S2 and S0), and magnetic resonance imaging of the brain (showing progressive cerebellar atrophy at 11 months of age). Conclusion. We describe a case report of CDG-Ia in a child from a family in which both parents are carriers of mutant alleles and have a healthy child. Despite comprehensive patient management, progressive disease course was observed; the girl has severe psychomotor retardation and clinical signs of multisystem involvement of internal organs. Arresting disease progression is not feasible due to the underlying genetic defect in the synthesis of mannose and glycoproteins, which are essential components of most metabolic pathways in the body.
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.
2026-01-01 | 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.
2025-12-23 | Clinical and genetic characterization of congenital disorders of glycosylation in 20 Chinese patients
BACKGROUND: Congenital disorders of glycosylation (CDG) are a complex and heterogeneous family of rare metabolic diseases that affect protein and lipid glycosylation and glycosylphosphatidylinositol synthesis. These disorders can affect multiple organs, leading to a broad spectrum of symptoms that vary among different CDG subtypes and between individuals with same type of CDG. This study aimed to investigate the genetic variants, molecular etiologies, and clinical features of 20 Chinese patients diagnosed with CDG. RESULTS: Using whole-exome sequencing (WES), functional prediction tools, Sanger sequencing, and segregation analysis, we identified variants in several genes: ALG2 (3 patients), DPM2 (3 patients), PMM2 (3 patients), and ALG13 (2 patients). Additionally, variants in COG5, COG6, MOGS, DPM3, ALG1, ALG3, ALG11, SSR4 and SLC35A2 each were observed in single case. In total, 28 distinct variants were identified, 11 of which were previously unreported. Genotype-phenotype correlations revealed notable findings: variants in the N-terminus of ALG2 before the intramembrane domain were associated with congenital myasthenic syndromes (CMS), whereas those in the C-terminus caused ALG2-CDG; DPM2-CDG patients with variants in transmembrane region 1 exhibited more severe phenotypes; male patients with hemizygous variants in SLC35A2 demonstrated milder phenotypes compared to those with mosaic variants. CONCLUSIONS: This findings expand the spectrum of known clinical presentations and genetic variants in CDG, and establish possible genotype-phenotype correlations of several pathogenic genes, emphasizing the need for functional studies to unravel the underlying mechanisms.
2025-12-15 | Identification of Two Siblings with PMM2-Congenital Disorder of Glycosylation Using Exome Sequencing in South East of Iran: Clinical and Genetic Findings
Background: Congenital disorders of glycosylation (CDG) encompass a broad spectrum of rare inborn errors of metabolism (IEMs), resulting in defective glycosylation of various proteins and/or lipids. PMM2-CDG is the most prevalent subtype of CDG, characterized by gene mutations leading to deficiency of the phosphomannomutase 2 (PMM2) enzyme. This research identified two Iranian patients from a consanguineous family with multiple organ dysfunctions, diagnosed with PMM2-CDG due to a pathogenic variant in the PMM2 gene. The study underscores the importance of identifying specific variants in different ethnic groups for effective genetic counseling for this disorder. Methods: The study utilized exome sequencing (ES) to identify pathogenic variants. Verification of the potential variant in affected siblings, along with segregation analysis involving the parents, affected individuals, and healthy siblings of the family, was performed using Sanger sequencing. Interpretation of the variant was informed by multiple in silico analysis tools, as well as by adhering to the guidelines set forth by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). Results: In the genomic investigations of the two brothers with intellectual disability (ID) and progressive movement disability, the NM_000303.3:c.647A > T (NP_000294.1:p.Asn216Ile) homozygous variant in the PMM2 gene was identified. The variant was confirmed in the affected and other family members by segregation analysis. Multiple in silico tools supported the pathogenic classification of the identified variant. Conclusions: The findings provide broader insight into variants within the PMM2 gene and offer a thorough characterization of the phenotype related to this specific variant. The data have important applications for genetic diagnosis and counseling in relevant clinical contexts, as well as for identifying common gene variants associated with various ethnic groups. Additionally, this information could serve as a valuable resource in guiding therapeutic interventions.
small molecules
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).
2025-10-23 | Treatment of Single Patient With PMM2‐Congenital Disorder of Glycosylation With Govorestat (AT‐007), an Aldose Reductase Inhibitor
Aldose reductase inhibitors (ARI) have been identified as a potential treatment for phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG), a serious condition for which no treatments are approved. We treated a single patient for 36 months 30 months of age at enrollment, under a single-patient investigational new drug expanded access request, with govorestat (AT-007), a novel, highly selective, once daily, brain penetrant ARI at a starting dose of 1 mg/kg oral suspension, which was escalated to 30 mg/kg. The primary endpoint was safety. Secondary assessments included liver transaminases, factor XI, antithrombin III, and whole blood and urine sorbitol. Clinical outcomes were also assessed, including Nijmegen Pediatric CDG Rating Scale (NPCRS), Bayley Scales of Infant Development, and Vineland Adaptive Behavioral Scale. Govorestat was well tolerated; no adverse effects were noted. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels improved from a pre-treatment 12-month average of 205 and 268 U/L to 63 and 68 U/L, respectively, averaged over 36 months of govorestat treatment at 30 mg/kg. Antithrombin III and factor XI fluctuated with illness throughout the study period but overall increased by 60%-100%, approaching the normal range (> 83% activity) at the 5 mg/kg dose. Whole blood sorbitol decreased in a dose-dependent fashion, normalizing at the 30 mg/kg dose. The NPCRS improved by 9 points (46%) over the course of treatment. In conclusion, our patient tolerated govorestat without safety concerns. Improvements in liver transaminases, clotting factors, and whole blood sorbitol were observed along with improvements in clinical measures. These findings support further study of govorestat as a potential treatment for PMM2-CDG.
2025-10-15 | Treatment of Single Patient With PMM2-Congenital Disorder of Glycosylation With Govorestat (AT-007), an Aldose Reductase Inhibitor.
Aldose reductase inhibitors (ARI) have been identified as a potential treatment for phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG), a serious condition for which no treatments are approved. We treated a single patient for 36 months 30 months of age at enrollment, under a single-patient investigational new drug expanded access request, with govorestat (AT-007), a novel, highly selective, once daily, brain penetrant ARI at a starting dose of 1 mg/kg oral suspension, which was escalated to 30 mg/kg. The primary endpoint was safety. Secondary assessments included liver transaminases, factor XI, antithrombin III, and whole blood and urine sorbitol. Clinical outcomes were also assessed, including Nijmegen Pediatric CDG Rating Scale (NPCRS), Bayley Scales of Infant Development, and Vineland Adaptive Behavioral Scale. Govorestat was well tolerated; no adverse effects were noted. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels improved from a pre-treatment 12-month average of 205 and 268 U/L to 63 and 68 U/L, respectively, averaged over 36 months of govorestat treatment at 30 mg/kg. Antithrombin III and factor XI fluctuated with illness throughout the study period but overall increased by 60%-100%, approaching the normal range (> 83% activity) at the 5 mg/kg dose. Whole blood sorbitol decreased in a dose-dependent fashion, normalizing at the 30 mg/kg dose. The NPCRS improved by 9 points (46%) over the course of treatment. In conclusion, our patient tolerated govorestat without safety concerns. Improvements in liver transaminases, clotting factors, and whole blood sorbitol were observed along with improvements in clinical measures. These findings support further study of govorestat as a potential treatment for PMM2-CDG.
2025-10-07 | Exploring Secondary Biotinidase Deficiency and Biotin Supplementation in PMM2-CDG.
The congenital disorders of glycosylation (CDG) encompass >190 multiorgan disorders with predominantly neurodevelopmental phenotypes with no causative treatment available. The glycoprotein biotinidase (BTD) provides biotin, an essential cofactor for carboxylases in ubiquitous metabolic pathways. Individuals with (partial) BTD deficiency (BTDD) and CDG patients show overlapping phenotypes like movement disorders, seizures, and neurodevelopmental issues. Biotin is a water-soluble, inexpensive, and safe food supplement. Patients with primary BTDD respond well to oral biotin supplement. We here explore secondary BTDD and the effect of biotin supplementation in PMM2-CDG in an initial open-label study.BTD activity in dried blood spots from 29 individuals with PMM2-CDG indicated a mean reduction to 27% (range: 23.0-40.5%) at group level. Patients (mean: 19.6 ± 11.9 years) were supplemented with 10 mg biotin daily for 12 months. The parents/caretaker reported positive responses in 62 to 69% of patients across seven (performance, social, at home, self-control, self-care, leisure, health) of the nine categories covered by the Adaptive Behavior Assessment System-II (ABAS-II) questionnaires. The reported positive effect of biotin supplementation differed between age groups, ranging from 54% (16-43 years) via 62% (2-5 years) to 80% (6-13 years). Its effect was reported to be the highest in the moderate to severely affected patient subgroups, with significant improvements in home functioning, health, performance, leisure, self-control. No adverse effects were reported.Given the absence of other treatments, the supportive effect of Biotin in PMM2-CDG deserves further exploration.
2025-10-01 | SUN-616 Phosphomannomutase 2 (PMM2)-Congenital Disorder of Glycosylation in a Patient with Dandy Walker Malformation
Abstract Disclosure: M. Kazim: None. S.S. Krishnasamy: None. Background: (PMM2)-congenital disorder of glycosylation (CDG) is a disorder of protein N-glycosylation characterized by deficiency/dysfunction of PMM2. We present a case of a patient with Dandy Walker Malformation (DWM) presenting with severe persistent hypoglycemia. Clinical Case: We were consulted on 24 y old African American female known case of DWM, congenital bilateral hearing loss, epilepsy, cerebral palsy, primary ovarian failure and, venous thromboembolism (VTE) for evaluation of persistent hypoglycemia. At birth she was in the NICU for hypoglycemia however since then she did not have any documented symptomatic hypoglycemia. Patient now presented with hypoglycemic symptoms after recent hospitalization for VTE and renal infarct. Labs showed ACTH 7 pg/mL, AM cortisol 10.2 mcg/dL, glucose 50mg/dl, C-peptide of 1.97 ng/ml, proinsulin 47 pmol/L, insulin 18.1 uIU/ml, Prolactin 10.4 ng/ml, TSH 1.71 mIU/L, Free T4 1.1 ng/dL, IGF-1 343 ng/mL, FSH 160 mIU/mL, LH 63.2 mIU/mL. CT abdomen and pelvis showed no pathology of the pancreas. Patient was hospitalized with severe hypoglycemia not responding to D10 infusion. Given hyper insulinemic hypoglycemia resistant to intravenous dextrose we initiated diazoxide 3 mg/kg q8h. she was also started on glucocorticoids for suspicion of autoimmune etiology of hypoglycemia. She responded quite well with improving blood sugars. She was referred to genetics given no clear cause of hypoglycemia established. Carbohydrate deficient transferrin test showed increased Mono-Oligo/Di-Oligo ratio of 0.32 (normal <0.06) and A-Oligo/Di-Oligo Ratio of 0.123 (normal <0.011). Patient is now on a stable regimen with diazoxide 100mg by mouth every 6 hours and high protein/complex carbohydrate diet with improvement of hypoglycemia. Conclusion: CDG are a wide spectrum of disorders associated with dysfunction of multiple organs particularly the brain and endocrine system. Cerebellar atrophy has been reported in 95.4% of cases with PMM2- CGD with the most common cerebellar symptom in patients being ataxia (1). To our knowledge only one other case has been published with PMM2- CDG and Dandy Walker Malformation (DWM). Due to paucity of cases involving CDG and DWM it is unclear if DWM is a separate entity in these patients or caused by CDG itself. CDG should be considered as a differential in patients with DWM presenting with hypoglycemia even in later aspect of life. Reference: (1)Altassan R, Péanne R, Jaeken J, et al. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up [published correction appears in J Inherit Metab Dis. 2019 May;42(3):577. doi: 10.1002/jimd.12082]. J Inherit Metab Dis. 2019;42(1):5-28. doi:10.1002/jimd.12024 Presentation: Sunday, July 13, 2025
cell therapies
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.
2025-05-08 | Targeted metabolomic evaluation of peripheral blood mononucleated cells from patients with PMM2-CDG.
Phosphomannomutase-2 (PMM2) deficiency represents the most common congenital disorder of glycosylation (CDG). Currently, little is known about cell metabolic alterations occurring in these patients. Here, we quantified compounds connected to protein glycosylation (GDP-mannose, UDP-derivatives), energy metabolism (high-energy phosphates, nicotinic coenzymes, oxypurines), oxidative/nitrosative stress (GSH, nitrite, nitrate) and free amino acids in extracts of peripheral blood mononucleated cells (PBMCs), of seven PMM2-CDG patients and ten control healthy donors. Besides marked GDP-mannose decrease, PBMCs of PMM2-CDG patients had higher UDP-glucose (UDP-Glc), UDP-galactose (UDP-Gal) and UDP-Glucuronic levels, lower ATP, GTP and UTP levels, abnormal ATP/ADP, ATP/AMP and NAD+/NADH ratios, increased xanthine, uric acid and nitrite + nitrate levels, and decreased GSH and free amino acids concentrations. These results suggest a new, conceivable metabolic route leading to the increase of specific UDP-derivatives (UDP-Glc, UDP-Gal and UDP-Glucuronic), also potentially explaining the glycogen abnormalities recently found in PMM2-CDG patients. Altogether, this study highlighted various metabolic changes caused by PMM2 deficiency, illustrating the widespread effects of PMM2 mutations (beyond N-glycan biosynthesis) that may significantly vary depending on the cell line considered. Using PBMCs, as a cellular model of lower invasiveness than skin fibroblast, may advantage cell metabolism studies to investigate new therapies specifically targeted to PMM2 deficiency.
2023-04-25 | Liver transplantation recovers hepatic N-glycosylation with persistent IgG glycosylation abnormalities: Three-year follow-up in a patient with phosphomannomutase-2-congenital disorder of glycosylation.
Phosphomannomutase-2-congenital disorder of glycosylation (PMM2-CDG) is the most common CDG and presents with highly variable features ranging from isolated neurologic involvement to severe multi-organ dysfunction. Liver abnormalities occur in in almost all patients and frequently include hepatomegaly and elevated aminotransferases, although only a minority of patients develop progressive hepatic fibrosis and liver failure. No curative therapies are currently available for PMM2-CDG, although investigation into several novel therapies is ongoing. We report the first successful liver transplantation in a 4-year-old patient with PMM2-CDG. Over a 3-year follow-up period, she demonstrated improved growth and neurocognitive development and complete normalization of liver enzymes, coagulation parameters, and carbohydrate-deficient transferrin profile, but persistently abnormal IgG glycosylation and recurrent upper airway infections that did not require hospitalization. Liver transplant should be considered as a treatment option for PMM2-CDG patients with end-stage liver disease, however these patients may be at increased risk for recurrent bacterial infections post-transplant.
2022-05-06 | Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation
Congenital disorders of glycosylation (CDG) are inherited metabolic diseases characterized by mutations in enzymes involved in different steps of protein glycosylation, leading to aberrant synthesis, attachment or processing of glycans. Recently, immunological dysfunctions in several CDG types have been increasingly documented. Despite these observations, detailed studies on immune cell dysfunction in PMM2-CDG and other CDG types are still scarce. Studying PMM2-CDG patient immune cells is challenging due to limited availability of patient material, which is a result of the low incidence of the disease and the often young age of the subjects. Dedicated immune cell models, mimicking PMM2-CDG, could circumvent many of these problems and facilitate research into the mechanisms of immune dysfunction. Here we provide initial observations about the immunophenotype and the phagocytic function of primary PMM2-CDG monocytes. Furthermore, we assessed the suitability of two different glycosylation-impaired human monocyte models: tunicamycin-treated THP-1 monocytes and PMM2 knockdown THP-1 monocytes induced by shRNAs. We found no significant differences in primary monocyte subpopulations of PMM2-CDG patients as compared to healthy individuals but we did observe anomalous surface glycosylation patterns in PMM2-CDG patient monocytes as determined using fluorescent lectin binding. We also looked at the capacity of monocytes to bind and internalize fungal particles and found a slightly increased uptake of C. albicans by PMM2-CDG monocytes as compared to healthy monocytes. Tunicamycin-treated THP-1 monocytes showed a highly decreased uptake of fungal particles, accompanied by a strong decrease in glycosylation levels and a high induction of ER stress. In contrast and despite a drastic reduction of the PMM2 enzyme activity, PMM2 knockdown THP-1 monocytes showed no changes in global surface glycosylation levels, levels of fungal particle uptake similar to control monocytes, and no ER stress induction. Collectively, these initial observations suggest that the absence of ER stress in PMM2 knockdown THP-1 cells make this model superior over tunicamycin-treated THP-1 cells and more comparable to primary PMM2-CDG monocytes. Further development and exploitation of CDG monocyte models will be essential for future in-depth studies to ultimately unravel the mechanisms of immune dysfunction in CDG.
other
2025-10-06 | Immunopathology in PMM2-CDG: Defective glycosylation impact in the TNFα -TNFR1 signalling pathway.
Glycosylation is a post-translational modification that plays a crucial role in immune system activity. Phosphomannomutase 2-Congenital Disorder of Glycosylation (PMM2-CDG) is a rare genetic disease affecting glycosylation with a multi-systemic impact. PMM2-CDG patients commonly show immune disfunction and elevated pro-inflammatory cytokine levels that may link to other symptoms. However, the underlying immune mechanisms remain unclear. Given Tumour Necrosis Factor (TNF)'s key role in inflammation, this study proposes that defective glycosylation of its receptors disrupts intracellular signalling, leading to changes in the immune response of PMM2-CDG patients. To address this, we applied an integrative approach, combining transcriptomics, glycomics, and immune-related assays to investigate the impact of TNF-a stimulation via TNF receptor 1 (TNFR1) in a cohort of PMM2-CDG patients' skin fibroblasts. Our results reveal a multifaceted disruption of TNF-a signalling in PMM2-CDG fibroblasts. We observed structural abnormalities in TNFR1, including altered receptor shedding. PMM2-CDG cells also showed an altered N-glycosylation profile, affecting particularly, high mannose N-glycans. At transcriptional level, PMM2-CDG cells, especially those bearing the R141H heterozygous variant, exhibited a distinct gene expression profile, after stimulation, characterized by dysregulation of immune and signalling pathways. Functionally, these molecular alterations translated into a diminished secretion of key inflammation and infection mediators, such as interleukin-6 (IL-6) and C-C Motif chemokine ligand 5 (CCL5) upon TNF-a stimulation. Similarly, essential signalling kinases including extracellular-signal-regulated kinase (ERK) 1/2, p38 and c-Jun N- terminal kinase (JNK) 2 showed reduced expression in PMM2-CDG cells, and their expression did not alter following TNF-a stimulation, unlike control cells. Our findings point to TNFR1 signalling dysregulation as a key contributor to immune dysfunction in PMM2-CDG. Importantly, our study identifies TNFR1 as a promising therapeutic target, suggesting that strategies aimed at modulating TNFR1 activity or restoring glycosylation homeostasis could provide new approaches for treatment development. This work advances our understanding of PMM2 -CDG immunopathology and opens opportunities for targeted therapeutics.
2023-06-02 | A liposomal carbohydrate vaccine, adjuvanted with an NKT cell agonist, induces rapid and enhanced immune responses and antibody class switching
Congenital disorders of glycosylation (CDGs) are genetic diseases caused by gene defects in glycan biosynthesis pathways, and there is an increasing number of patients diagnosed with CDGs. Because CDGs show many different clinical symptoms, their accurate clinical diagnosis is challenging. Recently, we have shown that liposome nanoparticles bearing the ALG1-CDG and PMM2-CDG biomarkers (a tetrasaccharide: Neu5Ac-α2,6-Gal-β1,4-GlcNAc-β1,4-GlcNAc) stimulate a moderate immune response, while the generated antibodies show relatively weak affinity maturation. Thus, mature antibodies with class switching to IgG are desired to develop high-affinity antibodies that may be applied in medical applications.In the present study, a liposome-based vaccine platform carrying a chemoenzymatic synthesized phytanyl-linked tetrasaccharide biomarker was optimized. The liposome nanoparticles were constructed by dioleoylphosphatidylcholine (DOPC) to improve the stability and immunogenicity of the vaccine, and adjuvanted with the NKT cell agonist PBS57 to generate high level of IgG antibodies. The results indicated that the reformulated liposomal vaccine stimulated a stronger immune response, and PBS57 successfully induce an antibody class switch to IgG. Further analyses of IgG antibodies elicited by liposome vaccines suggested their specific binding to tetrasaccharide biomarkers, which were mainly IgG2b isotypes.Immunization with a liposome vaccine carrying a carbohydrate antigen and PBS57 stimulates high titers of CDG biomarker-specific IgG antibodies, thereby showing great potential as a platform to develop rapid diagnostic methods for ALG1-CDG and PMM2-CDG.
2019-08-07 | Hypolipidaemia among patients with PMM2-CDG is associated with low circulating PCSK9 levels: a case report followed by observational and experimental studies
Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel therapeutics for reducing low-density lipoprotein cholesterol (LDLc). While serious side-effects have not been observed in short-term clinical trials, there remain concerns that long-term PCSK9 inhibition may cause neurocognitive side-effects. Methods and results An adult male with childhood-onset global developmental delay, cerebellar atrophy and severe hypolipidaemia underwent extensive biochemical and genetic investigations. Initial testing revealed low circulating PCSK9 levels and a common loss-of-function PCSK9 polymorphism, but these findings did not fully account for severe hypolipidaemia. Whole-exome sequencing was subsequently performed and identified two pathogenic phosphomannose mutase 2 (PMM2) variants (p.Arg141His and p.Pro69Ser) known to cause PMM2-associated congenital disorder of glycosylation (PMM2-CDG). A diagnosis of PMM2-CDG was consistent with the proband’s neurological symptoms and severe hypolipidaemia. Given that PMM2-CDG is characterised by defective protein N-glycosylation and that PCSK9 is a negative regulator of LDLc, we postulated that loss of PCSK9 N-glycosylation mediates hypolipidaemia among patients with PMM2-CDG. First, in an independent cohort of patients with PMM2-CDG (N=8), we verified that circulating PCSK9 levels were significantly lower in patients than controls (p=0.0006). Second, we conducted in vitro experiments in hepatocyte-derived cells to evaluate the effects of PCSK9 N-glycosylation loss on LDL receptor (LDLR) activity. Experimental results suggest that defective PCSK9 N-glycosylation reduces the ability of circulating PCSK9 to degrade LDLR. Conclusion Life-long exposure to genetically lower PCSK9 per se is unlikely to cause neurocognitive impairment. Both observational and experimental findings suggest that hypolipidaemia in PMM2-CDG may be partially mediated by loss of PCSK9 N-glycosylation and/or its regulators.
2006-07-06 | Recurrent infections and immunological dysfunction in congenital disorder of glycosylation Ia (CDG Ia)
Summary Congenital disorder of glycosylation Ia is the most common defect of glycosylation and is due to mutations in phosphomannomutase 2. This leads to aberrant N‐linked oligosaccharides. The phenotype of CDG Ia reflects the essential nature of glycosylation and patients typically present with multiple organs affected, with hypotonia, developmental delay, inverted nipples and abnormal fat pads. Later features include retinitis pigmentosa, stroke, cerebellar atrophy and malabsorption. Approximately 20% of patients die in the first year of life and infection is the most common cause of death. Immunological function has not previously been investigated in these patients and the critical role of oligosaccharides on adhesion molecules suggested that haematopoietic cell migration and communication could be disrupted by mutations in phosphomannomutase 2. We characterized the clinical features, performed standard immunological evaluations, and performed specific analyses of neutrophil adhesion molecules on two patients to address this question. Patient neutrophils had diminished chemotaxis but expressed comparable levels of adhesion molecules and rolled on artificial endothelium equivalently to control neutrophils. The most significant feature of the patients’ immunological function was poor vaccine responses. These two affected patients were begun on intravenous immunoglobulin with some improvement in their infections.
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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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