Congenital Disorder of Glycosylation

Congenital disorders of glycosylation (CDG) constitute a heterogeneous group of rare, inherited metabolic diseases characterised by defective glycosylation of proteins and lipids. These multisystem disorders, previously termed carbohydrate-deficient glycoprotein syndromes, disrupt essential cellular processes that rely on correct glycan assembly. As glycosylation is required for the normal function of a wide range of tissues, CDGs typically manifest with severe, often life-threatening abnormalities affecting the nervous system, musculature, gastrointestinal system and other organs. More than 130 subtypes have been recognised, with PMM2-CDG being the most prevalent form.

Background and Biological Basis

Glycosylation refers to the enzymatic attachment of carbohydrate structures to proteins or lipids, a modification that influences protein folding, cellular localisation, intermolecular interactions and metabolic stability. N-linked glycosylation, in which oligosaccharides are attached to asparagine residues, is one of the most biologically significant forms. Its biosynthetic pathway involves over a hundred enzymes, including glycosyltransferases, glycosidases, transporters and regulatory proteins.
All N-linked glycans begin as a lipid-linked oligosaccharide (LLO) precursor assembled on a dolichol-phosphate anchor within the endoplasmic reticulum. The oligosaccharide is subsequently transferred to a nascent polypeptide chain and undergoes extensive trimming and remodelling in the endoplasmic reticulum and Golgi apparatus. Defects in any step of this pathway may lead to CDG. Because carbohydrate-binding molecules, such as lectins and selectins, depend on correct glycan structure for their function, abnormal glycosylation has profound effects on immunity, development and cellular communication.

Clinical Presentation and Key Features

Clinical manifestations vary widely depending on the causative gene defect. Many patients present during infancy with signs involving the central nervous system, gastrointestinal tract, endocrine system and musculoskeletal system. Common features include:

• Ataxia and seizures
• Intellectual disability and developmental delay
• Retinopathy and other ocular abnormalities
• Liver dysfunction
• Coagulopathy
• Skeletal anomalies and hypotonia
• Failure to thrive
• Dysmorphic characteristics, such as inverted nipples or subcutaneous fat pads
• Pericardial effusion

Neuroimaging frequently reveals cerebellar hypoplasia. Ocular involvement in PMM2-CDG may take the form of myopia, infantile oesotropia, strabismus, nystagmus, optic disc pallor or reduced rod cell function on electroretinography. Peripheral neuropathy is also common.
Certain subtypes, including PMM2-CDG, PMI-CDG and ALG6-CDG, are associated with congenital hyperinsulinism leading to hypoglycaemia in early infancy. Defective glycosylation additionally affects multiple developmental pathways, contributing to cognitive impairment and delayed psychomotor progression.
Some variants, such as SSR4-CDG, have been reclassified as connective tissue disorders owing to characteristic musculoskeletal and extracellular matrix abnormalities.

Classification and Diagnostic Approaches

Historically, CDGs were divided into Type I and Type II categories based on abnormalities detected in transferrin glycosylation relative to the action of oligosaccharyltransferase. Type I patterns indicate disrupted synthesis or transfer of the LLO precursor, while Type II patterns reflect defective processing of glycan chains already attached to proteins.
Although this biochemical classification remains useful in clinical practice, contemporary nomenclature focuses on the underlying gene defect. Each subtype is named according to the mutated gene followed by the suffix “-CDG”, for example PMM2-CDG, PMI-CDG or ALG6-CDG. This shift reflects the identification of defects not only in glycan-synthetic enzymes but also in auxiliary proteins such as COG-complex components and vesicular transport proteins.
Diagnostic evaluation typically includes serum transferrin isoelectric focusing, mass spectrometry of glycoproteins and targeted or genome-wide molecular genetic testing. Given that a large proportion of the human genome contributes to glycosylation pathways, it is likely that further CDG types remain undiscovered.

Type I Defects: Impaired LLO Synthesis and Transfer

Type I disorders involve disruption of early steps in N-linked glycosylation, particularly in the construction or utilisation of the LLO precursor. These defects include:

• DPAGT1-CDG, caused by deficiency of GlcNAc-1-P transferase.
• ALG1-CDG, resulting from loss of the first mannosyltransferase.
• ALG2-CDG, involving impaired addition of the second and third mannose residues.
• ALG11-CDG, affecting addition of the fourth and fifth mannose residues.
• ALG3-CDG, due to mannosyltransferase VI deficiency.
• ALG9-CDG, stemming from defects in mannosyltransferase VII/IX.
• ALG12-CDG, involving mannosyltransferase VIII deficiency.
• ALG6-CDG and ALG8-CDG, caused by deficient glucosyltransferases I and II, respectively.

The most common subtype, PMM2-CDG (formerly CDG-Ia), is characterised by loss of phosphomannomutase-2, the enzyme responsible for conversion of mannose-6-phosphate into mannose-1-phosphate, a precursor of GDP-mannose required for LLO synthesis.

Type II Defects: Disordered Glycan Processing

Type II disorders arise from impairment of glycan trimming, modification or maturation after transfer to a protein backbone. Following attachment by the oligosaccharyltransferase complex, oligosaccharides are processed by a series of glycosidases and glycosyltransferases, enabling the creation of high-mannose, hybrid and complex-type glycan structures.
Defects in this phase include:

• CDG-IIb, due to loss of the first glycosidase (GCS1).
• MGAT2-CDG, involving deficiency of GlcNAc transferase II.
• SLC35C1-CDG, caused by GDP-fucose transporter deficiency, leading to impaired fucosylation and increased susceptibility to infection.
• B4GALT1-CDG, resulting from defective galactosyltransferase activity.
• COG7-CDG, linked with disruption of the conserved oligomeric Golgi (COG) complex.
• SLC35A1-CDG, due to deficient CMP-sialic acid transport.

These defects may interrupt multiple biosynthetic branches, resulting in complex and variable phenotypes.

Disorders of O-Mannosylation

A subset of CDGs affects glycosylation pathways other than N-linked glycosylation, including O-mannosylation of proteins. Defects in this category often present as muscular dystrophy–dystroglycanopathies (MDDG), encompassing a spectrum of conditions defined by the severity of muscular, ocular and cerebral involvement.
A widely accepted classification distinguishes three severity groups—A (severe), B (intermediate) and C (mild)—with genetic subtypes numbered according to the mutated gene:

1. POMT1
2. POMT2
3. POMGNT1
4. FKTN
5. FKRP
6. LARGE

Associated clinical entities include Walker–Warburg syndrome and muscle–eye–brain disease.

Additional Glycosylation-Related Disorders

Broader application of gene-based nomenclature has expanded CDG classification to include conditions involving other glycan pathways:

• EXT1/EXT2-CDG, linked with hereditary multiple exostoses.
• B4GALT7-CDG, associated with a progeroid variant of Ehlers–Danlos syndrome.
• B3GALTL-CDG, corresponding to Peters plus syndrome.
• LFNG-CDG, identified in spondylocostal dysostosis.

These disorders highlight the extensive role of glycosylation in skeletal development, extracellular matrix regulation and embryogenesis.

Treatment and Management

Therapeutic options for CDG remain limited, with most interventions focusing on supportive management of complications. However, a small number of subtypes respond to substrate supplementation:

• Mannose therapy has demonstrated efficacy in PMI-CDG, improving metabolic and clinical parameters, although hepatic fibrosis may persist.
• Fucose supplementation has yielded partial clinical benefit in SLC35C1-CDG.
• Emerging research suggests that ibuprofen may offer therapeutic benefit in at least one CDG subtype, although further studies are required to validate this observation.