Congenital Disorders of Glycosylation (CDG)

A. Definition and Pathophysiology

CDGs are a group of rare, inherited metabolic disorders affecting the synthesis and attachment of glycans to proteins and lipids.
Glycosylation is essential for protein folding, stability, trafficking, and cell signaling.
CDGs are classified by the affected pathway:
- N-glycosylation (most common)
- O-glycosylation
- Lipid glycosylation
- GPI-anchor biosynthesis
- Combined defects
CDG should be considered in any patient with unexplained liver dysfunction or multisystem involvement.

B. Genetics and Inheritance

Most CDGs are autosomal recessive; some are X-linked or autosomal dominant.
Over 130 genes have been implicated.
PMM2-CDG (CDG-Ia) is the most common subtype.
MPI-CDG (CDG-Ib) is treatable with oral mannose.

C. Clinical Presentation

Multisystem involvement is common and variable:
- Neurologic: Developmental delay, seizures, hypotonia, ataxia, stroke-like episodes, strabismus
- Hepatic: Hepatomegaly, steatosis, fibrosis, protein-losing enteropathy
- Cardiac: Cardiomyopathy, pericardial effusion, structural defects
- Gastrointestinal: Diarrhea, reflux, failure to thrive
- Endocrine: Hypoglycemia, hypothyroidism, delayed puberty
- Hematologic: Coagulopathy, thrombosis, bleeding diathesis
- Ophthalmologic: Strabismus, retinitis pigmentosa
- Skeletal: Dysplasia, scoliosis, arachnodactyly
- Skin: Cutis laxa, lipodystrophy

D. Histopathology

Liver biopsy findings may include:
- Steatosis
- Expanded portal tracts
- Hamartomatous bile duct proliferation
- Fibrosis or cirrhosis in advanced cases

E. Laboratory Findings

Biochemical abnormalities vary by subtype:
- Elevated liver enzymes
- Hypoalbuminemia
- Coagulation defects
- Hypoglycemia
- Abnormal thyroid function

F. Diagnostic Workup

Transferrin isoelectric focusing (TIEF): Detects abnormal glycoforms (Type I or II pattern)
Mass spectrometry: For glycan profiling
Genetic testing: Whole-exome sequencing or targeted panels
Enzyme assays: For treatable forms like MPI-CDG
Brain MRI: May show cerebellar hypoplasia or stroke-like lesions

G. Management

No cure for most CDGs; treatment is supportive and multidisciplinary.
MPI-CDG: Treated with oral mannose
PGM1-CDG and SLC35A2-CDG: May respond to galactose supplementation
Supportive care includes:
- Nutritional support (NG/G-tube, specialized formulas)
- Physical, occupational, and speech therapy
- Antiepileptics for seizures
- Hormone replacement (thyroid, insulin)
- Coagulation factor replacement
- Vision and orthopedic interventions

H. Prognosis

Highly variable depending on subtype and severity
Some children have mild symptoms and normal cognition
Others may have life-threatening complications
Early diagnosis and tailored management improve outcomes