Why Diagnosis Matters

Congenital Disorders of Glycosylation (CDG) are a large group of rare inherited diseases caused by defects in glycosylation—the process by which sugar chains (glycans) attach to proteins and lipids. Since these sugar modifications are vital for almost every function in the body, CDG can present with symptoms in multiple organs, from the nervous system to the liver, immune system, and heart.

Because symptoms overlap with many other diseases, accurate diagnosis is essential. Without proper testing, families may face years of uncertainty or misdiagnosis. A confirmed diagnosis not only explains the cause of symptoms but also guides treatment, family planning, and in some cases, access to clinical trials.

Initial Clinical Evaluation

The first step in diagnosing CDG is careful clinical evaluation. Pediatricians and specialists often suspect CDG when a child presents with a combination of neurological, developmental, and systemic symptoms.

Doctors typically look for:

  • Developmental delay and hypotonia (low muscle tone)

  • Failure to thrive or poor growth

  • Liver enlargement or abnormal liver function

  • Unexplained blood clotting problems

  • Unusual fat distribution or facial features

  • Recurrent infections

Because these features can occur in many conditions, doctors must rule out other causes before proceeding to specific CDG testing.

Family and Genetic History

Since CDG is inherited, family history plays an important role. A detailed review of the family tree may reveal:

  • Parents who are carriers of genetic mutations

  • Siblings with similar symptoms

  • Patterns of inheritance suggesting autosomal recessive or X-linked transmission

This information helps doctors decide which diagnostic tests are most appropriate.

Laboratory Blood Tests

Blood work is often the first major diagnostic step. Several laboratory markers raise suspicion of CDG:

  • Transferrin isoform analysis: The most widely used screening test. Transferrin is a glycoprotein, and abnormal glycosylation patterns indicate CDG.

  • Abnormal clotting factors: Some clotting proteins require glycosylation to function properly.

  • Liver enzyme levels: Elevated enzymes may suggest liver dysfunction associated with CDG.

  • Low blood sugar: In some forms, abnormal glycosylation affects insulin regulation.

These tests cannot identify the exact gene mutation but strongly suggest further evaluation.

Isoelectric Focusing of Transferrin

Isoelectric focusing (IEF) is considered a “gold standard” screening tool for CDG. It analyzes the charge differences in transferrin molecules, which change depending on how many glycans are attached.

  • CDG-I pattern: Missing entire glycans, often due to early defects in glycosylation.

  • CDG-II pattern: Abnormal processing or trimming of glycans.

While highly useful, IEF may not detect all types of CDG, especially rare subtypes.

Mass Spectrometry and HPLC

Advances in technology now allow more precise measurement of glycoproteins.

  • Mass spectrometry (MS): Provides detailed information about glycan structures on transferrin and other proteins.

  • High-performance liquid chromatography (HPLC): Separates and quantifies glycosylated forms.

These tests can detect subtle abnormalities missed by isoelectric focusing and are increasingly used in specialized labs.

Enzyme Activity Assays

Because CDG results from defective enzymes, testing enzyme function directly can confirm diagnosis.

Examples include:

  • PMM2 enzyme activity test: Used for PMM2-CDG, the most common subtype.

  • MPI enzyme activity test: Helps identify MPI-CDG, a type sometimes treatable with mannose supplements.

By showing reduced or absent enzyme activity, these assays pinpoint the biochemical cause of disease.

Genetic Testing

Genetic testing is the most definitive way to diagnose CDG. Modern sequencing technologies allow doctors to identify specific gene mutations responsible for the disorder.

  • Targeted gene sequencing: Focuses on known CDG-related genes when symptoms suggest a particular subtype.

  • Whole-exome sequencing (WES): Examines all protein-coding regions of DNA to find mutations in less common genes.

  • Whole-genome sequencing (WGS): Provides the most comprehensive analysis, sometimes revealing novel mutations.

Genetic confirmation not only finalizes the diagnosis but also helps with prognosis, family counseling, and potential participation in clinical research.

Imaging Studies

While imaging cannot diagnose CDG alone, it provides supportive evidence by showing structural or functional changes in affected organs.

  • Brain MRI: May reveal cerebellar atrophy, white matter abnormalities, or delayed myelination.

  • Liver ultrasound: Can show hepatomegaly or fatty changes.

  • Cardiac imaging: Echocardiograms may detect cardiomyopathy or structural heart defects.

These imaging findings help differentiate CDG from other neurological and metabolic disorders.

Specialized Organ Evaluations

Because CDG affects multiple body systems, additional evaluations are often performed:

  • Neurological exams: To assess developmental progress, seizures, and coordination.

  • Endocrine evaluations: To check hormone imbalances such as thyroid or growth hormone deficiency.

  • Ophthalmology exams: To detect strabismus, retinal degeneration, or other vision problems.

  • Audiology tests: To identify hearing loss, which may affect speech development.

Together, these evaluations paint a full picture of how CDG affects the child.

Differential Diagnosis

Many other conditions can mimic CDG, making differential diagnosis critical. Doctors may first consider:

  • Mitochondrial disorders

  • Peroxisomal disorders

  • Muscular dystrophies

  • Metabolic liver diseases

Excluding these possibilities ensures CDG is not diagnosed incorrectly.

Diagnostic Challenges

Despite advances, diagnosing CDG remains challenging for several reasons:

  1. Rarity of the disease: Many doctors have never seen a case, leading to misdiagnosis.

  2. Symptom variability: Even within the same subtype, symptoms can differ widely.

  3. Incomplete testing availability: Some advanced tests are only available in specialized centers.

  4. Cost and time: Genetic testing may be expensive and take weeks or months.

These challenges often delay diagnosis, emphasizing the need for greater awareness among healthcare providers.

Newborn Screening Potential

At present, CDG is not included in most national newborn screening programs. However, researchers are exploring whether mass spectrometry or genetic panels could one day make early detection routine.

Early screening would allow immediate intervention, better monitoring, and improved quality of life for affected children.

Confirming the Diagnosis

A confirmed CDG diagnosis usually requires combining multiple lines of evidence:

  • Abnormal transferrin or glycoprotein tests

  • Reduced enzyme activity in laboratory assays

  • Genetic testing showing mutations in a CDG-related gene

This multi-step process ensures accuracy and helps doctors classify the disorder into its correct subtype.

Why Early Diagnosis Matters

Early diagnosis allows:

  • Tailored treatment plans and supportive care

  • Access to dietary therapies (e.g., mannose for MPI-CDG, galactose for certain subtypes)

  • Better management of seizures, clotting issues, and hormonal imbalances

  • Genetic counseling for family planning

  • Participation in clinical trials for new therapies

Ultimately, timely diagnosis helps families find answers, receive support, and give children the best chance for healthier outcomes.