Congenital Disorder of Glycosylation

Congenital disorders of glycosylation (CDG) are a large group of more than 150 inherited disorders of the synthesis and attachment of glycans to proteins and lipids. They cause multisystem disease with neurological, hepatic, endocrine, haematological and immune involvement, and are classified by gene as, for example, PMM2-CDG and MPI-CDG.

Pathophysiology. Glycosylation depends on nucleotide sugar synthesis, transport into the endoplasmic reticulum and Golgi, assembly of lipid linked oligosaccharides and processing in the Golgi. Defects of assembly and transfer (earlier type I) give an abnormal serum transferrin pattern of disialo- and asialo forms, whereas defects in processing (earlier type II) give a different pattern.

Most are autosomal recessive; some are X-linked or dominant.

A small number are treatable by sugar supplementation, which makes early diagnosis important.

• Neurological: developmental delay, hypotonia, cerebellar hypoplasia and ataxia, seizures, stroke like episodes
• Hepatic: raised transaminases, fibrosis, coagulopathy (low antithrombin, protein C, factor XI)
• Gastrointestinal: vomiting, protein losing enteropathy, failure to thrive
• Endocrine: hypothyroidism, hyperinsulinaemic hypoglycaemia, hypogonadism
• Haematological: bleeding and thrombosis
• Eye: strabismus, retinitis pigmentosa, cataracts
• Cardiac: pericardial effusion and cardiomyopathy
• Renal: tubulopathy and cysts
• Immune: infections, and neutropenia in some
• Skin and fat: abnormal fat distribution, inverted nipples, and skin laxity
• Skeletal: scoliosis and osteopenia

• Serum transferrin analysis: carbohydrate deficient transferrin by isoelectric focusing, capillary electrophoresis or mass spectrometry. Normal results do not exclude every CDG, and false results occur in galactosaemia, hereditary fructose intolerance, and alcohol use.
• Exome or genome sequencing, or a CDG gene panel, with deletion and duplication analysis.
• Enzyme assays (PMM2, MPI) in leukocytes or fibroblasts for specific disorders.
• Apolipoprotein C-III isoelectric focusing and N-glycan profiling when transferrin is normal.
• Brain MRI (cerebellar atrophy), echocardiography and ophthalmology.
• Liver tests, coagulation studies, antithrombin and protein C, thyroid function, and glucose.

Differential diagnosis.

• Mitochondrial disease
• Galactosaemia and hereditary fructose intolerance (false positive transferrin)
• Other causes of cerebellar ataxia with developmental delay
• Congenital infections
• Other causes of coagulopathy with liver disease

• General principle: a coordinated multidisciplinary programme with a metabolic specialist.
• Treatable disorders: MPI-CDG responds to D-mannose; PGM1-CDG to D-galactose; SLC35C1-CDG to fucose; and other disorders to specific supplements, so confirm the gene before starting treatment.
• Coagulopathy: check antithrombin, protein C and factor XI. Before surgery, plan with a haematologist and give fresh frozen plasma 10 to 15 mL/kg for bleeding. Avoid prolonged immobilisation, and consider low molecular weight heparin prophylaxis in high risk periods.
• Stroke like episodes: hydration, avoidance of fever and dehydration, and supportive care.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, with other agents by seizure type. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Feeding and nutrition: dietitian input, tube feeding for failure to thrive, and omeprazole 0.7 to 1 mg/kg daily.
• Endocrine care: levothyroxine for hypothyroidism, diazoxide for hyperinsulinism, and sex steroid replacement as indicated.
• Eye care: correction of strabismus and monitoring for retinal disease.
• Infection: vaccination and prompt treatment.
• Development and communication: early intervention, physiotherapy, and special education.
• Genetic counselling: a 25% recurrence risk for autosomal recessive disorders, with prenatal diagnosis once the familial variants are known; X-linked and dominant forms follow their own inheritance.

Special groups.

• Infants with unexplained liver disease, coagulopathy and hypotonia: send transferrin analysis early, because a treatable disorder (MPI-CDG) may be present.

Monitoring. Liver tests, coagulation studies and thyroid function every 3 to 6 months. Growth, development and eye review yearly, and echocardiography as indicated.

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