RARE DISEASE
MPI-CDG
MPI-CDG
MPI-CDG
Synonyms: CDG syndrome type Ib, CDG-Ib, CDG1B, Carbohydrate deficient glycoprotein syndrome type Ib, Congenital disorder of glycosylation type 1b, Congenital disorder of glycosylation type Ib, Phosphomannose isomerase deficiency
Synonyms: CDG syndrome type Ib, CDG-Ib, CDG1B, Carbohydrate deficient glycoprotein syndrome type Ib, Congenital disorder of glycosylation type 1b, Congenital disorder of glycosylation type Ib, Phosphomannose isomerase deficiency
Synonyms: CDG syndrome type Ib, CDG-Ib, CDG1B, Carbohydrate deficient glycoprotein syndrome type Ib, Congenital disorder of glycosylation type 1b, Congenital disorder of glycosylation type Ib, Phosphomannose isomerase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
MPI-CDG (Mannose Phosphate Isomerase Congenital Disorder of Glycosylation) is a rare autosomal recessive disorder caused by pathogenic MPI gene variants, disrupting N-glycosylation. It primarily manifests with hepatic fibrosis, protein-losing enteropathy, hyperinsulinemic hypoglycemia, and coagulopathy, notably lacking neurological involvement [1][4]. Oral mannose supplementation is disease-modifying, improving gastrointestinal and hematologic symptoms, though progressive liver complications may persist [1][6]. Mortality rates approach 24% in untreated cases, predominantly from hepatic failure or sepsis in early childhood [1][2].
Burden
23.5% mortality in historical cohorts, primarily from hepatic complications/sepsis [1][2]
Chronic liver fibrosis, recurrent thrombotic events, and lifelong dietary/management compliance challenges despite therapy [1][6][12]
Requires multidisciplinary metabolic, hepatology, and nutrition monitoring [11][13]
Therapies
Oral mannose (150–170 mg/kg 4–5× daily): Restores glycosylation, reverses enteropathy/hypoalbuminemia, and prevents thrombosis [6][12]
Supportive care: Albumin infusions, anticoagulation for coagulopathy, endoscopic surveillance for portal hypertension [3][12]
Liver transplantation: Considered for progressive liver failure or hepatopulmonary syndrome [9][13]
Categories: rare gastroenterological diseases, rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
86 drug discovery papers about MPI-CDG, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
86 drug discovery papers about MPI-CDG, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-11-01 | Protein losing enteropathy due to congenital disorder of glycosylation: A case report
Protein-Losing Enteropathy (PLE) is the loss of protein through the gastrointestinal tract, subsequently leading to low levels of protein in the serum. The differential diagnosis for PLE is broad, and treatment is based on identifying and appropriately treating the underlying cause of the PLE. A 2-year-old boy presented with diarrhea, vomiting, edema, anemia, hypoalbuminemia, low serum IgG, and elevated stool alpha-1-antitrypsin, concerning for PLE. Endoscopy/colonoscopy showed mild reactive changes in the gastric and duodenal mucosa and was otherwise normal with no evidence of autoimmune enteropathy. MRI abdomen was negative for mesenteric lymphatic malformations. Echocardiogram showed a structurally normal heart. Urine CMV PCR was positive, and he was treated with valganciclovir for suspected Menetrier’s disease, with no improvement in symptoms. He was incidentally noted to be hypoglycemic and subsequently admitted with profoundly labile blood glucose requiring glucagon and continuous glucose infusions. Further workup demonstrated hyperinsulinism, up-trending liver enzymes with normal international normalized ratio, and coagulopathy with low factor 11 and antithrombin with PICC-associated DVT. The constellation of PLE, transaminitis, hyperinsulinemic hypoglycemia, and coagulopathy was concerning for a congenital disorder of glycosylation (CDG). Transferrin glycosylation studies showed a CDG type I pattern and were confirmed via genetic testing with biallelic variants in the mannose phosphate isomerase (MPI) gene, which established the diagnosis of mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG). Mannose therapy resulted in complete resolution of his edema, diarrhea, hypoalbuminemia, transaminitis, and hypoglycemia. CDGs include over 100 monogenic diseases with defects in the synthesis of oligosaccharides. Though a rare cause of PLE, MPI-CDG is an important consideration in the differential given the availability of an effective therapy. Treatment is well-tolerated and highly effective. In the case presented, the patient began showing symptomatic and biochemical improvement within a week of initiating therapy.
2025-11-01 | Oral D-mannose therapy during pregnancy in a woman with MPI-CDG: A case report and management review.
Mannose 6-phosphate isomerase deficiency is a rare disorder of N-glycosylation leading to impaired coagulation, enteropathy, hypoglycemia and liver disease. D-mannose is the only available treatment. We report the case of a pregnant woman with MPI-CDG and the management of D-mannose therapy during pregnancy. D-mannose was discontinued at 6 weeks' gestation, due to the potential fetal toxicity observed particularly in animal models, but severe digestive symptoms and hypoglycemia relapsed. We decided to readminister D-mannose therapy at 10 weeks' gestation although data on teratogenecity in humans are lacking. Symptoms resolved rapidly when D-mannose was resumed. Monitoring of transferrin glycoforms profile and coagulation parameters allowed to gradually increase D-mannose dosage throughout pregnancy. The patient delivered at 38 weeks' gestation after an intrauterine growth retardation was noted. The infant was 2.390 kg at birth with a low Apgar score but rapidly recovered. Low dose D-mannose treatment administered from 10 weeks' gestation could be a safe option for women with MPI-CDG.
2025-09-18 | [Clinical characteristics and D-mannose treatment outcomes in 5 children with mannose phosphate isomerase-congenital disorders of glycosylation].
Objective: To analyze the clinical characteristics of mannose phosphate isomerase-congenital disorders of glycosylation (MPI-CDG) and evaluated the outcomes following D-mannose treatment. Methods: This case-series study analyzed clinical manifestations, laboratory findings, imaging results, genetic data, and outcomes after D-mannose therapy in 5 children with MPI-CDG diagnosed at the Children's Hospital of Fudan University between December 2014 and December 2024. Results: The age of onset ranged from 0.3 to 0.4 years in all 5 children, who initially presented with diarrhea and hypoglycemia. Associated manifestations included short stature (3 cases), anemia (3 cases), splenomegaly (3 cases), hepatomegaly (4 cases), elevated transaminases (4 cases), and hypoalbuminemia (4 cases). Liver pathology revealed hepatic fibrosis in 3 cases. Genetic testing identified 8 variants in the MPI gene, including 2 novel variants. Following D-mannose treatment, diarrhea and hypoglycemia resolved within 1-2 weeks in all children, with concurrent improvement in anemia. Notably except for Patient 1, who developed progressive splenomegaly, worsening hepatic fibrosis, and portal hypertension despite persistently normal transaminase and albumin levels, the other 4 children showed improvement in transaminase levels, resolution of hypoalbuminemia and amelioration of imaging abnormalities. Conclusions: MPI-CDG typically manifests in infancy with diarrhea and hypoglycemia, often accompanied by multi-system involvement. D-mannose treatment significantly improves metabolic abnormalities and most organ damages. However, close surveillance of liver status is warranted due to the risk of hepatic fibrosis progression in some cases.
2025-07-23 | A hypomorphic Mpi mutation unlocks an in vivo tool for studying global N-glycosylation deficiency.
Glycans are one of the 4 major macromolecules essential for life and are the most abundant family of organic molecules. However, in contrast with DNA and RNA, glycan structures have no template; this results in limited tools to study this challenging macromolecule with a diversity of glycan structures. A central bottleneck in studying glycosylation in vivo is that inhibitors and complete KOs are lethal. In a forward genetic screen, we identified a viable, hypomorphic mutation at a conserved site in mannose phosphate isomerase (Mpi) that causes a multisystemic phenotype affecting RBCs, liver, stomach, intestines, skin, size, fat, and fluid balance in mice. The phenotype could be rescued with mannose. Analyses of glycopeptides in mice with this mutation showed a 500% increase in unoccupied N-glycan sites. This is equivalent to a "glycan knockdown," which would be useful for examining the role of glycans in biology and disease. Therefore, we report an in vivo tool to study global N-glycosylation deficiency with tissue-specific targeting and a rescue mechanism with mannose.
2025-06-01 | N-linked and O-linked glycoprotein biosynthesis in the endoplasmic reticulum and Golgi apparatus: Quality control mechanisms and disease associations
Glycosylation represents the most common and complex post-translational modification affecting protein folding, stability, and function. This research examined quality control mechanisms governing N-linked and O-linked glycoprotein biosynthesis with focus on disease-associated defects. Comprehensive literature analysis was integrated with experimental validation using glycosylation-deficient cell models. The calnexin/calreticulin cycle emerged as the central quality control checkpoint with glucosidase II and UDP-glucose:glycoprotein glucosyltransferase serving as folding sensors. Systematic analysis of congenital disorders of glycosylation revealed that specific clinical phenotypes map to defined enzymatic deficiencies throughout the biosynthetic pathway. N-glycan profiling of patient-derived fibroblasts confirmed characteristic glycan structural abnormalities associated with each enzyme defect. O-linked glycosylation defects, though less commonly recognized, contributed to muscular dystrophy and other developmental disorders through impaired protein function. Therapeutic approaches including mannose supplementation for MPI-CDG and galactose supplementation for SLC35A2-CDG showed measurable biochemical improvement. Understanding quality control mechanisms illuminates disease pathophysiology while identifying intervention opportunities for this expanding group of metabolic disorders.
vaccines
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.
small molecules
2025-11-01 | Protein losing enteropathy due to congenital disorder of glycosylation: A case report
Protein-Losing Enteropathy (PLE) is the loss of protein through the gastrointestinal tract, subsequently leading to low levels of protein in the serum. The differential diagnosis for PLE is broad, and treatment is based on identifying and appropriately treating the underlying cause of the PLE. A 2-year-old boy presented with diarrhea, vomiting, edema, anemia, hypoalbuminemia, low serum IgG, and elevated stool alpha-1-antitrypsin, concerning for PLE. Endoscopy/colonoscopy showed mild reactive changes in the gastric and duodenal mucosa and was otherwise normal with no evidence of autoimmune enteropathy. MRI abdomen was negative for mesenteric lymphatic malformations. Echocardiogram showed a structurally normal heart. Urine CMV PCR was positive, and he was treated with valganciclovir for suspected Menetrier’s disease, with no improvement in symptoms. He was incidentally noted to be hypoglycemic and subsequently admitted with profoundly labile blood glucose requiring glucagon and continuous glucose infusions. Further workup demonstrated hyperinsulinism, up-trending liver enzymes with normal international normalized ratio, and coagulopathy with low factor 11 and antithrombin with PICC-associated DVT. The constellation of PLE, transaminitis, hyperinsulinemic hypoglycemia, and coagulopathy was concerning for a congenital disorder of glycosylation (CDG). Transferrin glycosylation studies showed a CDG type I pattern and were confirmed via genetic testing with biallelic variants in the mannose phosphate isomerase (MPI) gene, which established the diagnosis of mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG). Mannose therapy resulted in complete resolution of his edema, diarrhea, hypoalbuminemia, transaminitis, and hypoglycemia. CDGs include over 100 monogenic diseases with defects in the synthesis of oligosaccharides. Though a rare cause of PLE, MPI-CDG is an important consideration in the differential given the availability of an effective therapy. Treatment is well-tolerated and highly effective. In the case presented, the patient began showing symptomatic and biochemical improvement within a week of initiating therapy.
2025-11-01 | Oral D-mannose therapy during pregnancy in a woman with MPI-CDG: A case report and management review.
Mannose 6-phosphate isomerase deficiency is a rare disorder of N-glycosylation leading to impaired coagulation, enteropathy, hypoglycemia and liver disease. D-mannose is the only available treatment. We report the case of a pregnant woman with MPI-CDG and the management of D-mannose therapy during pregnancy. D-mannose was discontinued at 6 weeks' gestation, due to the potential fetal toxicity observed particularly in animal models, but severe digestive symptoms and hypoglycemia relapsed. We decided to readminister D-mannose therapy at 10 weeks' gestation although data on teratogenecity in humans are lacking. Symptoms resolved rapidly when D-mannose was resumed. Monitoring of transferrin glycoforms profile and coagulation parameters allowed to gradually increase D-mannose dosage throughout pregnancy. The patient delivered at 38 weeks' gestation after an intrauterine growth retardation was noted. The infant was 2.390 kg at birth with a low Apgar score but rapidly recovered. Low dose D-mannose treatment administered from 10 weeks' gestation could be a safe option for women with MPI-CDG.
2025-09-18 | [Clinical characteristics and D-mannose treatment outcomes in 5 children with mannose phosphate isomerase-congenital disorders of glycosylation].
Objective: To analyze the clinical characteristics of mannose phosphate isomerase-congenital disorders of glycosylation (MPI-CDG) and evaluated the outcomes following D-mannose treatment. Methods: This case-series study analyzed clinical manifestations, laboratory findings, imaging results, genetic data, and outcomes after D-mannose therapy in 5 children with MPI-CDG diagnosed at the Children's Hospital of Fudan University between December 2014 and December 2024. Results: The age of onset ranged from 0.3 to 0.4 years in all 5 children, who initially presented with diarrhea and hypoglycemia. Associated manifestations included short stature (3 cases), anemia (3 cases), splenomegaly (3 cases), hepatomegaly (4 cases), elevated transaminases (4 cases), and hypoalbuminemia (4 cases). Liver pathology revealed hepatic fibrosis in 3 cases. Genetic testing identified 8 variants in the MPI gene, including 2 novel variants. Following D-mannose treatment, diarrhea and hypoglycemia resolved within 1-2 weeks in all children, with concurrent improvement in anemia. Notably except for Patient 1, who developed progressive splenomegaly, worsening hepatic fibrosis, and portal hypertension despite persistently normal transaminase and albumin levels, the other 4 children showed improvement in transaminase levels, resolution of hypoalbuminemia and amelioration of imaging abnormalities. Conclusions: MPI-CDG typically manifests in infancy with diarrhea and hypoglycemia, often accompanied by multi-system involvement. D-mannose treatment significantly improves metabolic abnormalities and most organ damages. However, close surveillance of liver status is warranted due to the risk of hepatic fibrosis progression in some cases.
2025-07-23 | A hypomorphic Mpi mutation unlocks an in vivo tool for studying global N-glycosylation deficiency.
Glycans are one of the 4 major macromolecules essential for life and are the most abundant family of organic molecules. However, in contrast with DNA and RNA, glycan structures have no template; this results in limited tools to study this challenging macromolecule with a diversity of glycan structures. A central bottleneck in studying glycosylation in vivo is that inhibitors and complete KOs are lethal. In a forward genetic screen, we identified a viable, hypomorphic mutation at a conserved site in mannose phosphate isomerase (Mpi) that causes a multisystemic phenotype affecting RBCs, liver, stomach, intestines, skin, size, fat, and fluid balance in mice. The phenotype could be rescued with mannose. Analyses of glycopeptides in mice with this mutation showed a 500% increase in unoccupied N-glycan sites. This is equivalent to a "glycan knockdown," which would be useful for examining the role of glycans in biology and disease. Therefore, we report an in vivo tool to study global N-glycosylation deficiency with tissue-specific targeting and a rescue mechanism with mannose.
2025-06-01 | N-linked and O-linked glycoprotein biosynthesis in the endoplasmic reticulum and Golgi apparatus: Quality control mechanisms and disease associations
Glycosylation represents the most common and complex post-translational modification affecting protein folding, stability, and function. This research examined quality control mechanisms governing N-linked and O-linked glycoprotein biosynthesis with focus on disease-associated defects. Comprehensive literature analysis was integrated with experimental validation using glycosylation-deficient cell models. The calnexin/calreticulin cycle emerged as the central quality control checkpoint with glucosidase II and UDP-glucose:glycoprotein glucosyltransferase serving as folding sensors. Systematic analysis of congenital disorders of glycosylation revealed that specific clinical phenotypes map to defined enzymatic deficiencies throughout the biosynthetic pathway. N-glycan profiling of patient-derived fibroblasts confirmed characteristic glycan structural abnormalities associated with each enzyme defect. O-linked glycosylation defects, though less commonly recognized, contributed to muscular dystrophy and other developmental disorders through impaired protein function. Therapeutic approaches including mannose supplementation for MPI-CDG and galactose supplementation for SLC35A2-CDG showed measurable biochemical improvement. Understanding quality control mechanisms illuminates disease pathophysiology while identifying intervention opportunities for this expanding group of metabolic disorders.
vaccines
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.
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