Congenital Disorders of Glycosylation (CDG) are a group of over 130 rare, inherited metabolic disorders that result from defects in the glycosylation process. Glycosylation is a crucial biochemical function in which sugar molecules, known as glycans, are attached to proteins and lipids in cells. This process is essential for the structure, stability, and function of proteins throughout the body. When glycosylation is impaired, it leads to widespread dysfunction in multiple organs and systems.

CDG is typically diagnosed in infancy, although milder forms may not be recognized until later in childhood or adulthood. The condition most often affects the nervous system, but other organs such as the liver, heart, kidneys, and gastrointestinal tract can also be involved.

Types of CDG

Although more than 130 types of CDG have been identified, they are classified into four major categories based on the specific glycosylation pathway affected:

1. Disorders of Protein N-Glycosylation This is the most common form of CDG and includes PMM2-CDG (formerly CDG-Ia), which is the most frequently diagnosed type. It results from a defect in the enzymes responsible for adding glycans to the nitrogen atom of asparagine residues in proteins.

2. Disorders of Protein O-Glycosylation These disorders affect the enzymes that add glycans to the oxygen atom of serine or threonine residues. Some types of muscular dystrophy are linked to defects in this pathway.

3. Disorders of Glycosphingolipid and GPI-Anchor Glycosylation These affect glycosylation of lipid-linked molecules, such as glycosphingolipids and glycosylphosphatidylinositol (GPI) anchors. Such defects can result in complex and variable symptoms.

4. Disorders of Multiple Glycosylation Pathways In these cases, multiple glycosylation processes are impacted simultaneously. These mixed-type disorders often present with broader and more severe symptoms.

Signs and Symptoms

CDG manifests in a variety of ways depending on the type and severity. Neurological symptoms are among the most common, affecting brain function and motor control.

Common symptoms include:

  • Hypotonia (low muscle tone)

  • Developmental delays and intellectual disability

  • Ataxia and poor coordination

  • Seizures and stroke-like episodes

  • Abnormal fat distribution

  • Liver dysfunction

  • Heart issues such as cardiomyopathy, arrhythmias, and pericardial effusion

  • Blood clotting disorders or easy bruising

  • Distinctive facial features

  • Feeding difficulties and failure to thrive

  • Eye problems like strabismus

  • Skin abnormalities such as rashes or scaling

  • Immune deficiencies

Each individual with CDG may present a different combination and severity of these symptoms.

Underlying Causes

CDG is caused by mutations in specific genes involved in the glycosylation process. Most CDG cases are inherited in an autosomal recessive pattern, meaning a child must inherit a faulty gene from both parents.

Some rarer forms are autosomal dominant, requiring only one copy of the mutated gene to cause the disorder. Additionally, some mutations may occur spontaneously and are not inherited from either parent.

Risk Factors

If both parents carry a defective gene linked to CDG, each child has:

  • A 25% chance of being affected

  • A 50% chance of being a carrier

  • A 25% chance of being unaffected

If one parent carries a dominant mutation, the chance of passing it to offspring is 50% for each pregnancy. Spontaneous (de novo) mutations generally pose a low risk for siblings unless the mutation is inherited.

How CDG Is Diagnosed

Diagnosing CDG can be challenging due to its overlap with other disorders like cerebral palsy or mitochondrial diseases. A comprehensive approach is required, including:

1. Medical history and physical exam Detailed documentation of symptoms, growth charts, developmental milestones, and family history.

2. Blood tests

  • Transferrin isoform analysis (to detect glycosylation defects)

  • Mass spectrometry for glycoprotein abnormalities

3. Genetic testing Used to confirm a specific CDG type by identifying mutations in known genes.

4. Imaging and additional screenings MRI for cerebellar hypoplasia, echocardiograms for cardiac anomalies, and liver/kidney function tests.

Treatment and Management

While there is currently no cure for CDG, treatment is aimed at managing symptoms, improving quality of life, and supporting development. Treatment is tailored based on the individual's needs and the severity of their symptoms.

Treatment options may include:

  • Nutritional therapy, special formulas, or feeding tubes

  • Hormone replacement (e.g., for hypothyroidism)

  • Anti-epileptic drugs for seizure control

  • Anticoagulants or plasma infusions for clotting disorders

  • Cardiac medications or surgery for heart abnormalities

  • Physical, occupational, and speech therapy

  • Mannose or galactose supplementation for sugar-responsive CDG types

  • Vision correction with glasses or surgery

Early intervention and a multidisciplinary care team are essential for optimizing outcomes.

Prevention Strategies

CDG cannot be prevented if the mutation is inherited. However, prospective parents with a family history of CDG can consider genetic counseling and carrier screening.

Although current genetic tests can identify many known CDG mutations, they cannot detect all possible gene variants due to the condition's complexity and evolving gene catalog.

Related Conditions

Due to glycosylation’s central role in cellular function, CDG may be associated with or lead to several secondary conditions:

  • Ataxia: Unsteady movement and coordination due to cerebellar involvement

  • Epilepsy: Recurrent seizures affecting quality of life

  • Peripheral neuropathy: Muscle weakness and sensory loss in limbs

  • Cerebellar hypoplasia: Underdeveloped cerebellum leading to motor difficulties

  • Retinal degeneration: Vision loss due to glycosylation defects in eye tissue

  • Hypothyroidism: Low thyroid hormone levels

  • Pericardial effusion: Fluid accumulation around the heart

Living With CDG

Families managing CDG face significant emotional, financial, and logistical challenges. Support groups such as CDG CARE and other advocacy organizations offer valuable resources.

Helpful strategies include:

  • Joining family support networks

  • Working closely with a multidisciplinary medical team

  • Advocating for early intervention services

  • Participating in clinical trials if eligible

  • Monitoring for new treatment advancements

Although life expectancy and prognosis vary widely, many children with milder forms of CDG live into adulthood with proper care and ongoing management.