PMM2-CDG

PMM2-CDG (CDG-Ia) is the commonest congenital disorder of glycosylation, an autosomal recessive condition due to biallelic variants in PMM2 with deficiency of phosphomannomutase 2. It causes cerebellar hypoplasia, developmental delay, abnormal fat distribution, strabismus, and multisystem disease, with a spectrum from fatal infantile disease to mild adult disease.

Pathophysiology. Phosphomannomutase 2 converts mannose-6-phosphate to mannose-1-phosphate, which is needed for GDP-mannose and the dolichol linked oligosaccharide that is transferred to proteins. Reduced function leads to hypoglycosylation of many proteins.

Most patients carry at least one hypomorphic variant (p.Arg141His is common but lethal as homozygous).

Presentation and course vary between and within families.

• Hypotonia, poor feeding and failure to thrive in infancy
• Cerebellar hypoplasia with ataxia, hypotonia, and later intellectual disability
• Strabismus, nystagmus and retinitis pigmentosa
• Abnormal subcutaneous fat pads and inverted nipples in infancy
• Stroke like episodes and seizures, often with infection
• Coagulopathy with bleeding or thrombosis
• Hepatic dysfunction, protein losing enteropathy
• Hyperinsulinaemic hypoglycaemia in some
• Cardiac: pericardial effusion and cardiomyopathy
• Infantile mortality from infection or organ failure in severe disease
• Adult disease: peripheral neuropathy, scoliosis, hypogonadism, and retinitis pigmentosa

• Serum transferrin analysis: type 1 pattern (increased disialo- and asialotransferrin), which may be normal in some infants and in a few adults.
• PMM2 enzyme activity in leukocytes or fibroblasts.
• PMM2 sequencing with deletion and duplication analysis.
• Brain MRI: cerebellar hypoplasia with pontine atrophy.
• Liver tests, coagulation studies, antithrombin, protein C and factor XI.
• Echocardiography, thyroid function and ophthalmology.
• Prenatal ultrasound may show hydrops or cerebellar hypoplasia.

• Infant care: nutrition support, tube feeding if needed, and prompt treatment of infection. Provide a treatment plan for fever.
• Hypoglycaemia: diazoxide 5 to 15 mg/kg daily in three divided doses for hyperinsulinism, with glucose monitoring.
• Stroke like episodes: hydration and avoidance of fever. Seizures should be managed with levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Coagulopathy: haematology plan before procedures, with fresh frozen plasma 10 to 15 mL/kg for bleeding and prophylaxis against thrombosis in high risk periods.
• Pericardial effusion and heart disease: echocardiography, drainage for tamponade.
• Enteropathy: albumin infusion for severe hypoalbuminaemia and dietary fat modification.
• Eye care: strabismus surgery, and correction of refractive error.
• Endocrine care: thyroid replacement, growth monitoring and puberty induction with sex steroids in hypogonadism.
• Experimental treatment: epalrestat (an aldose reductase inhibitor) is under investigation for the neurological disease and is not established.
• Development and communication: early intervention, physiotherapy and special education.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Children undergoing anaesthesia or surgery: plan with haematology and cardiology, and avoid dehydration.

Monitoring. Growth, feeding and development every 3 months in infancy. Liver tests, coagulation studies and thyroid function every 6 months, and eye review and echocardiography yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine, neurology and haematology. Emergency for bleeding, thrombosis, sepsis, seizures or stroke like symptoms.