Carbohydrate Deficient Glycoprotein Syndrome (CDG) is the original name for what is now known as Congenital Disorders of Glycosylation. These disorders arise from errors in a fundamental cellular process common to nearly all body systems. The defects result in numerous health problems that can vary widely in severity. Since glycosylation is required for the proper function of cells throughout the body, CDG often presents with complex, multi-system involvement.
The Underlying Cause: Defects in Glycosylation
The core issue in CDG is a flaw in glycosylation, the process where sugar chains (glycans) are built and attached to proteins and lipids. This process creates functional glycoproteins and glycolipids, necessary for cellular signaling, structural support, and protein folding. Glycoproteins are responsible for functions such as blood clotting, immune response, and nervous system development.
Glycosylation involves hundreds of enzymes working in a precise sequence within the cell’s endoplasmic reticulum and Golgi apparatus. In CDG, a mutation exists in a gene that instructs the cell to make these enzymes. This defective enzyme cannot perform its job correctly, leading to the production of proteins and lipids with missing or incomplete sugar chains.
The resulting glycoproteins are considered “carbohydrate-deficient,” which impairs their ability to function normally in the body. Because these faulty proteins are involved in nearly every physiological process, the resulting syndrome affects almost all of the body’s organs and systems. The specific defective enzyme determines which sugar chains are affected and, consequently, the specific symptoms and severity of the condition.
Classification and Major Subtypes
CDG is not a single disease but an umbrella term encompassing over 130 recognized genetic disorders. The classification system groups these disorders based on the affected gene, often using the gene symbol followed by “-CDG.” Defects are broadly categorized by the location of the error, such as N-linked, O-linked, or lipid glycosylation defects.
The most frequent form of the condition is PMM2-CDG, formerly known as CDG-Ia, which accounts for the majority of diagnosed cases worldwide. This subtype is caused by a mutation in the PMM2 gene, resulting in a deficient phosphomannomutase 2 enzyme. This enzyme is responsible for an early step in the synthesis of N-linked glycans, providing an essential building block.
MPI-CDG, previously called CDG-Ib, results from a defect in the phosphomannose isomerase (MPI) enzyme. Unlike PMM2-CDG, MPI-CDG affects an enzyme metabolically upstream in the mannose pathway. The location of the defect often dictates the clinical presentation and the possibility of a specific therapeutic intervention.
Clinical Manifestations Across Body Systems
The wide-ranging functions of glycoproteins result in a broad spectrum of clinical manifestations, often involving multiple organ systems simultaneously. The central nervous system is frequently affected, leading to common symptoms. These include developmental delay, intellectual disability, hypotonia (low muscle tone), and cerebellar ataxia (problems with movement coordination). Seizures and stroke-like episodes, characterized by temporary paralysis and lethargy, are also reported in some individuals.
Hepatic and gastrointestinal issues are common, including liver dysfunction and feeding difficulties in infants. Some patients develop protein-losing enteropathy, where essential proteins leak from the gut. Endocrine abnormalities are also characteristic, often presenting as problems with hormone regulation, such as hypoglycemia and delayed or absent puberty.
Other systems are also affected:
- Skeletal and connective tissue involvement can manifest as scoliosis (abnormal curvature of the spine) and joint contractures.
- A classic physical sign, particularly in young children with PMM2-CDG, is the presence of inverted nipples and an unusual distribution of subcutaneous fat.
- Ocular issues are common, including strabismus (crossed eyes) and vision impairment due to conditions like retinitis pigmentosa.
- The coagulation system is affected because many clotting factors are glycoproteins, leading to a risk of both abnormal bleeding and the formation of dangerous blood clots.
Diagnosis and Genetic Confirmation
Diagnosing a suspected CDG involves a biochemical screening test that analyzes the serum protein transferrin. This test, often performed using Transferrin Isoelectric Focusing (TIEF) or similar techniques, reveals the glycosylation status of the protein. Transferrin normally carries four sugar chains, but defective glycosylation results in molecules with fewer or incomplete sugar chains.
The presence of these abnormal transferrin isoforms, known as carbohydrate-deficient transferrin, is a strong indicator of CDG. However, this abnormal pattern does not identify the precise genetic error. The definitive diagnosis and determination of the specific subtype require genetic testing.
Genetic sequencing identifies the specific mutation responsible for the glycosylation defect. This genetic confirmation is essential because the specific subtype dictates prognosis, management strategies, and the potential for a targeted treatment. Genetic analysis remains the gold standard for final confirmation.
Current Treatment and Management Strategies
Treatment for most Congenital Disorders of Glycosylation, especially the most common PMM2-CDG, focuses on a multidisciplinary approach to manage symptoms and prevent complications. Supportive care is the mainstay of treatment. This involves a team of specialists, including neurologists, endocrinologists, and physical therapists, to address issues like seizures, hormone deficiencies, and developmental delays.
Physical, occupational, and speech therapies are utilized to maximize developmental potential and improve motor skills. Coagulation factor replacement may be necessary to manage bleeding or clotting risks. Specialized feeding support is often required for severe gastrointestinal issues.
A few rare subtypes of CDG have specific, targeted therapies that can correct the underlying metabolic defect. MPI-CDG (CDG-Ib) can be successfully treated with oral D-mannose supplementation. Mannose bypasses the defective MPI enzyme, replenishing the necessary sugar building blocks. This simple sugar supplementation is ineffective for PMM2-CDG because the defect occurs at a different point in the metabolic pathway, emphasizing the need for accurate subtyping.