MPI-CDG

MPI-CDG (CDG-Ib) is a treatable autosomal recessive congenital disorder of glycosylation due to biallelic variants in MPI, with deficiency of phosphomannose isomerase. It presents with hepatic, gastrointestinal and coagulation disease but typically without intellectual disability, and responds to oral D-mannose.

Pathophysiology. Phosphomannose isomerase converts fructose-6-phosphate to mannose-6-phosphate. Deficiency reduces the supply of mannose for glycosylation. Oral mannose is converted to mannose-6-phosphate by hexokinase, which bypasses the block.

The condition is the main CDG presenting with gastrointestinal and hepatic features.

Untreated disease can be fatal in infancy.

• Protein losing enteropathy with oedema, diarrhoea and vomiting
• Hepatic fibrosis and cirrhosis, hepatomegaly, and portal hypertension
• Hyperinsulinaemic hypoglycaemia
• Coagulopathy with bleeding and thrombosis
• Failure to thrive and feeding difficulty
• Generally normal neurodevelopment, although mild features can occur
• Thrombotic events including stroke
• Hypoalbuminaemia
• Cholestasis, and congenital hepatic fibrosis

• Serum transferrin analysis: type 1 pattern.
• Phosphomannose isomerase activity in leukocytes or fibroblasts: reduced.
• MPI sequencing with deletion and duplication analysis.
• Liver tests, coagulation studies, antithrombin and protein C.
• Albumin, alpha-1 antitrypsin clearance in stool, and glucose monitoring.
• Liver ultrasound and endoscopy for portal hypertension.

Differential diagnosis.

• Other causes of protein losing enteropathy (Crohn disease, congenital lymphangiectasia)
• Other causes of congenital hepatic fibrosis and cholestasis
• Hereditary fructose intolerance and galactosaemia (false positive transferrin)
• PMM2-CDG and other CDG with neurological disease
• Hyperinsulinism from other causes

• D-mannose: 1 g/kg daily in five or six divided doses by mouth or gastrostomy, starting at 0.1 g/kg and increasing over days, adjusting by response in albumin, coagulation and transferrin. Adverse effects are diarrhoea and abdominal discomfort, and high doses can cause hyperglycaemia in vulnerable patients.
• Hypoglycaemia: diazoxide 5 to 15 mg/kg daily in three divided doses for hyperinsulinism, and frequent feeds. Check glucose after starting mannose because it can worsen hypoglycaemia in diseases of mannose metabolism.
• Hepatic fibrosis and portal hypertension: propranolol 1 mg/kg daily divided up to 4 mg/kg in children (adults 40 mg twice daily to 160 mg twice daily) and endoscopic banding for varices. Liver transplantation for decompensated disease, although it does not correct enteropathy.
• Coagulopathy: haematology plan before procedures, with fresh frozen plasma 10 to 15 mL/kg for bleeding.
• Enteropathy: albumin infusion for severe hypoalbuminaemia, and low fat diet.
• Nutrition: high energy feeds with dietitian input.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Infants with diarrhoea, oedema and coagulopathy: start mannose once the diagnosis is likely, without waiting for genetic confirmation.

Monitoring. Albumin, transaminases, coagulation tests and transferrin pattern every month at first, then every 3 to 6 months. Liver ultrasound yearly, and upper endoscopy if portal hypertension.

Referral and escalation. Refer to clinical genetics, metabolic medicine, hepatology and haematology. Emergency for bleeding, thrombosis, severe hypoglycaemia or variceal haemorrhage.