Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation

Abstract

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.

FIGURE 1

Scheme of mannose metabolism in MPI deficient cell. A, MPI deficiency causes metabolic block in endogenous pathway generating mannose. Under normal diet, the exogenous mannose is not sufficient to maintain normal intracellular mannose levels (less than 10 μmol/L in MPI-CDG patients compared to 50-100 μmol/L in healthy individuals) and results in protein N-hypoglycosylation. B, The enzymatic block can be bypassed by mannose therapy. Serum mannose level over 200 μmol/L normalises the protein glycosylation. However, the excessive mannose substitution can cause the intracellular energy failure induced by Man-6-P accumulation. The Man-6-P inhibits the HK, PGI, and Glc-6-P dehydrogenase activity, decreases level of glycolysis, causes depletion of intracellular ATP and subsequent energy failure. ADP, adenosine diphosphate; ATP, adenosine triphosphate; ER, endoplasmic reticulum; Fru-6-P, fructose-6-phosphate; HK, hexokinase; G6PD, glucose-6-phosphate dehydrogenase; GDP-Man, Guanosine diphosphate-mannose; Glc, glucose; Glc-1-P, glucose-1-phosphate; Glc-6-P, glucose-6-phosphate; Man, mannose; Man-1-P, mannose-1-phosphate; Man-6-P, mannose-6-phosphate; MPI, mannose phosphate isomerase; PGI, phosphoglucose isomerase; PGM1, phosphoglucomutase 1; PMM2, phosphomannomutase 2

FIGURE 2

The most common clinical features and laboratory abnormalities in MPI-CDG. The classic triad of symptoms in MPI-CDG associates digestive, hepatic, and endocrine symptoms, whereas the neurologic involvement is typically absent. The figure shows the list of the most common symptoms and their frequency before mannose treatment, which was calculated as a ratio of positive cases to all published cases with sufficient clinical information. The percentage is stated, only if more than 10 patients with a respective symptom were described. * Hyperinsulinaemic hypoglycaemia was documented in 10 out of 13 investigated patients. ** Confirmed on liver biopsy. CDG, congenital disorder of glycosylation; MPI, mannose phosphate isomerase