Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.

• Keywords
• d-galactose, PGM1-CDG, congenital disorder of glycosylation, management guidelines, phosphoglucomutase 1 deficiency,
• MeSH
• Adult MeSH
• Galactose therapeutic use   MeSH
• Glycogen Storage Disease complications   diagnosis   drug therapy   enzymology   MeSH
• Hypoglycemia complications   MeSH
• Cardiomyopathies complications   pathology   MeSH
• Infant MeSH
• Consensus MeSH
• Humans MeSH
• Disease Management * MeSH
• International Cooperation MeSH
• Muscular Diseases complications   pathology   MeSH
• Cleft Palate complications   pathology   MeSH
• Check Tag
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Practice Guideline MeSH
• Names of Substances
• Galactose MeSH

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.

• Keywords
• AT deficiency, MPI-CDG, guidelines, hepatic fibrosis, hyperinsulinaemic hypoglycaemia, mannose phosphate isomerase, protein-losing enteropathy,
• MeSH
• Consensus MeSH
• Humans MeSH
• Disease Management MeSH
• Mannose-6-Phosphate Isomerase deficiency   genetics   MeSH
• Practice Guidelines as Topic MeSH
• Congenital Disorders of Glycosylation diagnosis   enzymology   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Mannose-6-Phosphate Isomerase MeSH

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.

• Keywords
• CDG, PGM1-CDG, central carbon metabolism, galactose, glycosylation, mitochondria, nucleotide sugars, tracer metabolomics,
• MeSH
• Fibroblasts drug effects   metabolism   pathology   MeSH
• Phosphoglucomutase deficiency   MeSH
• Galactose administration & dosage   MeSH
• Glycosylation MeSH
• Cohort Studies MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Uridine Diphosphate Galactose metabolism   MeSH
• Uridine Diphosphate Glucose metabolism   MeSH
• Congenital Disorders of Glycosylation drug therapy   metabolism   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Phosphoglucomutase MeSH
• Galactose MeSH
• Uridine Diphosphate Galactose MeSH
• Uridine Diphosphate Glucose MeSH

PurposePhosphoglucomutase-1 deficiency is a subtype of congenital disorders of glycosylation (PGM1-CDG). Previous casereports in PGM1-CDG patients receiving oral D-galactose (D-gal) showed clinical improvement. So far no systematic in vitro and clinical studies have assessed safety and benefits of D-gal supplementation. In a prospective pilot study, we evaluated the effects of oral D-gal in nine patients.MethodsD-gal supplementation was increased to 1.5 g/kg/day (maximum 50 g/day) in three increments over 18 weeks. Laboratory studies were performed before and during treatment to monitor safety and effect on serum transferrin-glycosylation, coagulation, and liver and endocrine function. Additionally, the effect of D-gal on cellular glycosylation was characterized in vitro.ResultsEight patients were compliant with D-gal supplementation. No adverse effects were reported. Abnormal baseline results (alanine transaminase, aspartate transaminase, activated partial thromboplastin time) improved or normalized already using 1 g/kg/day D-gal. Antithrombin-III levels and transferrin-glycosylation showed significant improvement, and increase in galactosylation and whole glycan content. In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal lipid-linked oligosaccharide profile, and abnormal nucleotide sugars in patient fibroblasts. Most cellular abnormalities improved or normalized following D-gal treatment. D-gal increased both UDP-Glc and UDP-Gal levels and improved lipid-linked oligosaccharide fractions in concert with improved glycosylation in PGM1-CDG.ConclusionOral D-gal supplementation is a safe and effective treatment for PGM1-CDG in this pilot study. Transferrin glycosylation and ATIII levels were useful trial end points. Larger, longer-duration trials are ongoing.

• MeSH
• Administration, Oral MeSH
• Child MeSH
• Phosphoglucomutase metabolism   MeSH
• Galactose administration & dosage   adverse effects   therapeutic use   MeSH
• Glycogen Storage Disease drug therapy   MeSH
• Glycoproteins metabolism   MeSH
• Blood Coagulation MeSH
• Infant MeSH
• Creatine Kinase blood   MeSH
• Blood Glucose metabolism   MeSH
• Skin cytology   metabolism   MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Pilot Projects MeSH
• Child, Preschool MeSH
• Prospective Studies MeSH
• Transferrin metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Phosphoglucomutase MeSH
• Galactose MeSH
• Glycoproteins MeSH
• Creatine Kinase MeSH
• Blood Glucose MeSH
• PGM1 protein, human MeSH Browser
• Transferrin MeSH