Congenital Disorders of Glycosylation (CDG), formerly known as Carbohydrate-Deficient Glycoprotein Syndromes, are a group of rare inherited metabolic conditions. These disorders are caused by genetic mutations that disrupt a widespread cellular process called glycosylation, which involves attaching sugar chains to proteins and fats. Since properly formed glycoproteins are needed for the structure and function of most tissues and organs, CDG can cause a wide range of health problems, from mild to severe.
The Genetic and Cellular Basis of CDG
Glycosylation is a process inside cells that attaches complex sugar chains, called glycans, to proteins and lipids in a precise sequence. This modification helps proteins fold correctly, remain stable, and travel to their proper locations within or outside the cell. Without these sugar chains, many proteins cannot perform their designated functions.
CDG is caused by mutations in genes that code for the enzymes of the glycosylation pathway. Each gene provides instructions for a specific enzyme that performs one step in building and attaching the glycan chains. A mutation can result in a missing or defective enzyme, creating a bottleneck in the process.
When a glycosylation enzyme is faulty, the resulting glycoproteins may be missing their sugar chains or have incomplete structures. These improperly formed proteins cannot function correctly, leading to multi-systemic problems. The specific consequences depend on which enzyme is affected and how its absence disrupts glycoproteins throughout the body.
Recognizing the Symptoms
The symptoms of CDG and their severity vary significantly, even among individuals with the same genetic subtype. This variability can make diagnosis challenging, as the condition can affect nearly any part of the body. Signs are often apparent in infancy or early childhood.
Neurological problems are among the most common features of CDG and can include:
- Hypotonia (low muscle tone), which can delay motor skills like sitting and walking
- Developmental delays and intellectual disability
- Ataxia (a lack of voluntary muscle coordination), which can cause a staggering gait
- Seizures of various types
Certain physical features are often observed in individuals with CDG. These can include inverted nipples, an unusual distribution of fat appearing as pads on the buttocks or above the collarbone, and skeletal abnormalities like a short sternum. While not universal, these markers can point toward a glycosylation disorder.
CDG can also impact multiple internal organs. Liver involvement is common, ranging from elevated liver enzymes to severe disease. Heart problems may include pericardial effusion (fluid around the heart) or cardiomyopathy (weakening of the heart muscle). Kidney issues, vision problems like strabismus, and blood clotting abnormalities can also occur.
The Diagnostic Process
A CDG diagnosis often begins when a physician observes a combination of clinical symptoms. Because the signs are varied and overlap with other conditions, a specific biochemical test is used as a primary screening tool to investigate the glycosylation pathway.
The primary screening for CDG is a blood test analyzing a protein called transferrin. This test, known as transferrin isoelectric focusing, separates transferrin molecules by their electrical charge, which is determined by attached sugar chains. In many forms of CDG, transferrin is missing some sugar chains, altering its charge and creating an abnormal test pattern.
An abnormal transferrin test indicates a likely glycosylation disorder but does not provide a definitive diagnosis or identify the specific type. To confirm the diagnosis and determine the precise genetic cause, molecular genetic testing is required to find mutations in genes known to cause CDG. Pinpointing the exact gene and mutation confirms the diagnosis, classifies the subtype, and is important for genetic counseling and understanding prognosis.
Types and Classifications of CDG
CDG is an umbrella term for over 130 distinct genetic disorders. The classification system has evolved from a Type I/II grouping based on transferrin tests to a more precise convention based on the mutated gene. This results in names like PMM2-CDG, which identifies the specific gene involved.
The most common form is PMM2-CDG (formerly CDG-Ia), caused by mutations in the PMM2 gene. This type presents as a severe, multi-systemic disorder in infancy, with symptoms including developmental delay, ataxia, and liver dysfunction. It represents the form most commonly associated with the condition.
Other types show different features. For example, MPI-CDG (formerly CDG-Ib) is caused by MPI gene mutations and primarily affects the liver and gastrointestinal system, often without neurological impairment. In contrast, SLC35A2-CDG is an X-linked disorder associated with difficult-to-treat epilepsy from a young age, affecting males more severely. Identifying the genetic subtype is therefore important for prognosis and management.
Management and Therapeutic Approaches
There is currently no cure for most CDG types. Medical care focuses on managing symptoms and providing supportive therapies to improve quality of life. This requires a coordinated, multidisciplinary approach because the disorder affects many body systems.
An individual with CDG is cared for by a team of specialists. Regular follow-up is necessary to monitor for complications and adjust treatment, and the team may include:
- A neurologist to manage seizures and movement disorders
- A gastroenterologist to address liver and feeding issues
- A cardiologist to monitor heart function
- An ophthalmologist for vision problems
Supportive therapies are a key part of management. Physical therapy addresses hypotonia and improves motor skills, occupational therapy helps with daily activities, and speech therapy assists with communication and swallowing. These interventions are most effective when started early and tailored to the individual.
While most types of CDG only have symptomatic treatments, a few have specific therapies. For example, MPI-CDG can be treated with mannose supplementation, which may resolve many liver-related symptoms.