Congenital Disorders of Glycosylation (CDG) are a complex group of rare, inherited metabolic diseases. These disorders are caused by defects in the body’s ability to create or attach sugar molecules to proteins and lipids, a process called glycosylation. With over 130 subtypes identified, CDG are multi-system disorders that can affect nearly every organ and system in the body. Understanding these disorders provides insight into a fundamental biological process necessary for life.
Defining Congenital Disorders of Glycosylation
CDG is classified as an inborn error of metabolism, meaning the body lacks the necessary machinery to perform a specific chemical reaction correctly from birth. The defect lies in the intricate process of glycosylation, which involves the precise assembly and attachment of complex sugar chains, known as glycans, to thousands of different proteins and fats within the cells. These glycans are functional structures that determine the final shape, stability, and cellular destination of the proteins they are attached to.
When glycosylation is impaired, the resulting proteins, called glycoproteins, are improperly formed and cannot perform their intended roles, leading to widespread cellular malfunction. This cellular deficiency explains why CDG affects multiple organs simultaneously, as glycosylation is a universal process required in all cells. The severity of the disorder depends on which specific step of the pathway is affected and the degree of functional impairment.
How CDG Affects the Body Systems
The systemic nature of CDG means that symptoms are highly variable and affect multiple organ systems, often starting in infancy. The central nervous system is frequently involved, leading to a range of neurological issues that are often the most significant health challenge. Infants often present with hypotonia (low muscle tone) and developmental delays affecting motor skills and cognitive function. Many patients also experience seizures. A common finding on brain imaging is cerebellar hypoplasia, the underdevelopment of the cerebellum, resulting in difficulties with balance and coordination (ataxia).
Gastrointestinal and hepatic complications are common manifestations, often contributing to failure to thrive (inability to gain weight and grow). Liver involvement can range from elevated liver enzymes to severe liver disease. Furthermore, many blood clotting proteins are glycoproteins, and their improper formation can lead to coagulopathy, resulting in abnormal bleeding or an increased risk of blood clots (thrombosis).
CDG can also disrupt the endocrine and immune systems. Hypothyroidism (low thyroid hormone production) is a frequent finding, as are issues with sexual development, particularly in females who may not undergo puberty. The immune system’s reliance on properly glycosylated proteins means that frequent or recurrent infections can be a concern for many patients.
Beyond the major organ systems, skeletal and connective tissue problems are regularly observed. Skeletal abnormalities, such as scoliosis (abnormal curvature of the spine), may develop and progress over time, sometimes requiring orthopedic intervention. Other noticeable external features include an unusual distribution of fat tissue and crossed eyes (strabismus). Managing CDG requires a comprehensive, multidisciplinary approach to address the diverse symptoms.
Genetic Basis and Diagnostic Testing
The root cause of CDG lies in mutations within specific genes that code for the enzymes or transporters required for the glycosylation pathway. CDG is most commonly inherited in an autosomal recessive pattern, meaning an individual must inherit a mutated copy of the gene from both parents to be affected. The parents, who each carry only one faulty copy, are typically healthy carriers who do not exhibit symptoms. Currently, over 130 different genes have been identified, each corresponding to a different type of CDG.
The most frequent form is PMM2-CDG, caused by a mutation in the PMM2 gene. This gene provides instructions for making the enzyme phosphomannomutase 2, which is essential for an early step in the most common glycosylation process. The presence of many different genes involved explains the wide clinical variability seen across the entire CDG group.
Diagnosis often begins with biochemical screening tests when a combination of multi-system symptoms is observed. The initial, most widely used screening tool is the analysis of serum transferrin, a protein found in the blood. This test, often performed using Transferrin Isoelectric Focusing (TfIEF), detects whether the transferrin protein has the correct number of attached sugar chains. An abnormal pattern provides strong evidence of a CDG.
Molecular genetic testing is required for a definitive diagnosis and to identify the specific subtype. Genetic sequencing is used to pinpoint the exact mutation in the responsible gene. Identifying the precise genetic cause confirms the diagnosis, allows for accurate genetic counseling, and guides specific treatment decisions for the few subtypes that are responsive to targeted therapies.
Management and Current Treatment Approaches
For the majority of individuals with CDG, treatment focuses on supportive care aimed at managing the symptoms. This approach requires a large team of specialists, including neurologists, hematologists, and endocrinologists, to monitor and address the diverse health issues. Supportive interventions often include physical, occupational, and speech therapy to address developmental delays and muscle weakness.
Specific medical management is tailored to the individual’s symptoms. This may involve specialized feeding methods, such as a gastrostomy tube, to ensure proper nutrition and manage failure to thrive. Coagulopathy is managed by closely monitoring blood clotting factors, and replacement may be necessary before surgical procedures to prevent excessive bleeding. Seizures are managed with anti-convulsant medications, and hormonal issues like hypothyroidism are treated with hormone replacement therapy.
A small number of CDG subtypes are responsive to targeted dietary or supplement interventions. The most notable example is Mannose Phosphate Isomerase-CDG (MPI-CDG), a rare form that can be effectively treated with oral mannose supplementation. The mannose sugar bypasses the defective enzyme, restoring the normal glycosylation process and often leading to rapid improvement in severe gastrointestinal and hepatic problems. Other sugar-responsive types also exist, although their effects can be more variable.
Research continues to explore emerging therapeutic strategies that may address the underlying defect for common types, like PMM2-CDG. These efforts include clinical trials investigating substrate replacement therapies, where a necessary precursor molecule is supplied to the cell to circumvent the faulty enzyme. Advances in gene therapy and other novel approaches hold promise for future disease-modifying treatments.