Congenital disorders of glycosylation (CDG) are rare inherited disorders resulting from defects in cellular glycosylation machinery. Albumin has recently been shown to be N-glycosylated at two non-canonical glycosylation sites. We applied multiplexed mass spectrometry-based glycoproteomics to identify site-specific N-glycosylation alterations in albumin from patients with PMM2-CDG, MPI-CDG, SRD5A3-CDG, MAN1B1-CDG and PGM1-CDG. Our findings demonstrate that the glycosylation of albumin is indeed affected in CDG and indicate a potential role for albumin-derived glycopeptides as diagnostic biomarkers.

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. 目的： 分析磷酸甘露糖异构酶-先天性糖基化障碍（MPI-CDG）的临床特征及D-甘露糖治疗后的转归。 方法： 病例系列研究。分析2014年12月至2024年12月复旦大学附属儿科医院确诊的5例MPI-CDG患儿的临床、实验室检查、影像学检查、基因检测结果及D-甘露糖治疗后的转归。 结果： 5例患儿起病年龄为0.3~0.4岁，均以腹泻伴低血糖为首发表现，合并矮小症3例、贫血3例、脾脏肿大3例、肝脏肿大4例、转氨酶升高4例及低白蛋白血症4例。肝脏病理显示肝纤维化3例；基因检测发现8个MPI基因变异，其中2个为未报道的变异。经 D-甘露糖治疗所有患儿腹泻及低血糖在1~2周内缓解，贫血改善；例1出现脾脏进行性增大、肝纤维化进展并发生门静脉高压，但其转氨酶和白蛋白水平始终维持正常；而其余4例患儿的转氨酶升高、低白蛋白血症及肝脏影像学表现均获得改善。 结论： MPI-CDG多表现为婴儿期腹泻合并低血糖，常伴多系统受累，经D-甘露糖治疗可显著改善其代谢异常及多数器官损伤，但仍需注意密切随访肝脏变化，警惕肝纤维化发生与发展。.

Hereditary fructose intolerance (HFI) is characterized by liver damage and a secondary defect in N-linked glycosylation due to impairment of mannose phosphate isomerase (MPI). Mannose treatment has been shown to be an effective treatment in a primary defect in MPI (i.e., MPI-CDG), which is also characterized by liver damage. Therefore, the aims of this study were to determine: (1) hepatic nucleotide sugar levels, and (2), the effect of mannose supplementation on hepatic nucleotide sugar levels and liver fat, in a mouse model for HFI. Aldolase B deficient mice (Aldob-/-) were treated for four weeks with 5% mannose via the drinking water and compared to Aldob-/- mice and wildtype mice treated with regular drinking water. We found that hepatic GDP-mannose and hepatic GDP-fucose were lower in water-treated Aldob-/- mice when compared to water-treated wildtype mice (p = 0.002 and p = 0.002, respectively), consistent with impaired N-linked glycosylation. Of interest, multiple other hepatic nucleotide sugars not involved in N-linked glycosylation, such as hepatic UDP-glucuronic acid, UDP-xylose, CMP-N-acetyl-beta-neuraminic acid, and CDP-ribitol (p = 0.002, p = 0.003, p = 0.002, p = 0.002), were found to have altered levels as well. However, mannose treatment did not correct the reduction in hepatic GDP-mannose levels, nor was liver fat affected. Aldob-/- mice are characterized by hepatic nucleotide sugar abnormalities, but these were not abrogated by mannose treatment. Future studies are needed to identify the underlying mechanisms responsible for the abnormal hepatic nucleotide sugar pattern and intrahepatic lipid accumulation in HFI. Trial Registration: PCT ID: PCTE0000340, this animal experiment is registered at (https://preclinicaltrials.eu/).

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.

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.