Successful Liver Transplantation and Long-Term Follow-up in a Patient With MPI-CDG

Abstract

Hepatopathy is the most common feature in the Congenital Disorders of Glycosylation (CDG). More than 70 subtypes have been identified in this growing group of inborn errors. Most defects present as multisystem disease, whereas phosphomannose isomerase deficiency (MPI-CDG) presents with exclusive hepato-intestinal phenotype. MPI-CDG has been considered as one of the very few treatable disorders of glycosylation; several patients showed significant improvement of their life-threatening protein-losing enteropathy and coagulation disorder on oral mannose supplementation therapy. However, patients who have MPI-CDG develop progressive liver insufficiency during a later course of disease. A patient who had MPI-CDG developed progressive liver fibrosis, despite oral mannose supplementation and repeated fractionated heparin therapy. She showed mannose therapy-associated hemolytic jaundice. She developed severe dyspnea and exercise intolerance owing to pulmonary involvement, necessitating liver transplant. After transplantation her physical exercise tolerance, pulmonary functions, and metabolic parameters became fully restored. She is still doing well 2 years after transplantation now. In conclusion, we here report on the first successful liver transplantation in CDG.

Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans

“…Current therapeutic guidelines for oral mannose supplements to treat MPI-CDG range from 0.1 to 1.0 g/kg of body weight daily and has been demonstrated in MPI-CDG patients to result in dose-dependent serum mannose concentrations of 250-490 µM. (1,(3)(4)(5) In our study, this concentration has little effect on HSC expression of fibrogenic genes in culture ( Fig. 5).…”

“…Potential explanations for this lack of therapeutic response include: (1) irreversible, prolonged liver damage in utero and delay in diagnosis (MPI‐CDG is often diagnosed well after infancy); (2) a nonglycosylation function of MPI and mannose therapy; or (3) higher doses of mannose are required to reverse the fibrosis. Current therapeutic guidelines for oral mannose supplements to treat MPI‐CDG range from 0.1 to 1.0 g/kg of body weight daily and has been demonstrated in MPI‐CDG patients to result in dose‐dependent serum mannose concentrations of 250‐490 µM . In our study, this concentration has little effect on HSC expression of fibrogenic genes in culture (Fig.…”

“…Children with a congenital disorder of glycosylation (CDG) who lack the enzyme, mannose phosphate isomerase (MPI), have altered protein glycosylation and develop early, progressive liver fibrosis requiring transplantation. (1)(2)(3) This monogenic disease poignantly demonstrates that loss of MPI provokes liver fibrosis; however, the mechanisms underlying this effect are not known. MPI interconverts fructose 6-phosphate and mannose 6-phosphate (Fru6P ←→ Man6P; Supporting Fig.…”

Congenital disorders of glycosylation: new defects and still counting

“…); however, patients might develop early cirrhosis. Janssen et al 2014 reported the first successful liver transplantation in a patient with therapy-resistant MPI-CDG who showed mannose-therapy-associated hemolytic jaundice, progressive liver fibrosis, severe dyspnea, and exercise intolerance due to pulmonary involvement. Posttransplantation, her exercise tolerance, pulmonary functions, and metabolic parameters became fully restored, and she remained stable 2 years after transplantation.…”

A novel homozygous mutation in the mannose phosphate isomerase gene causing congenital disorder of glycation and hyperinsulinemic hypoglycemia in an infant

“…In CDG type Ib, liver fibrosis might appear in childhood or in young adulthood when liver failure may occur. Successful liver transplant has been reported in this condition 9. In one reported patient, severe hypoglycemia was the initial feature of presentation, but liver disease with coagulopathy subsequently developed highlighting the need for follow‐up of liver function 7.…”