Congenital Disorders of Glycosylation (CDG) represent a diverse group of rare genetic conditions. These disorders arise from defects in glycosylation, a fundamental biological process involving the attachment of sugar molecules to proteins and lipids. This disruption can impact the proper functioning of cells throughout the body, leading to a wide array of health challenges. CDG are not a single disease but rather a collection of over 160 known subtypes, each with its own unique genetic basis and clinical presentation.
Understanding Congenital Disorders of Glycosylation
Glycosylation is a complex, enzyme-catalyzed process where sugar chains, also known as glycans, are built and attached to proteins and lipids. These modified molecules, called glycoproteins and glycolipids, play widespread roles in cellular functions, including cell-to-cell communication, immune responses, and protein stability.
Congenital Disorders of Glycosylation occur when there are errors in this intricate glycosylation pathway. These errors stem from genetic mutations affecting one or more of the hundreds of genes involved in creating, modifying, or attaching these sugar chains. CDGs are broadly categorized into groups based on the affected pathway, such as N-linked glycosylation, O-linked glycosylation, or defects in glycosylphosphatidylinositol (GPI) anchor biosynthesis. For example, PMM2-CDG, the most common subtype, results from a defect in the PMM2 enzyme, which is involved in N-glycosylation.
How CDGs Impact the Body
The widespread importance of glycosylation means that defects in this process can affect nearly every organ system and bodily function. Symptoms often appear in infancy and can range significantly in severity, even among individuals with the same CDG subtype. The clinical features are highly variable, making CDGs a diagnostic challenge.
Neurological issues are common, affecting more than 80% of CDG patients. These can include developmental delays, intellectual disability, low muscle tone (hypotonia), and problems with balance and coordination (ataxia). Seizures and stroke-like episodes are also reported in various CDG types. Brain imaging frequently reveals structural abnormalities, such as an undersized cerebellum (cerebellar hypoplasia).
Liver dysfunction is another frequent manifestation, appearing as elevated liver enzymes or an enlarged liver (hepatomegaly). While liver disease is not always clinically significant, severe cases can lead to fibrosis or cirrhosis. Gastrointestinal problems are also common, including feeding difficulties, vomiting, diarrhea, and in some cases, protein-losing enteropathy.
Immune system deficiencies can lead to recurrent or severe infections, impacting the lungs and respiratory tract in some CDG types like FUT8-CDG. Skeletal abnormalities are also widely observed, including scoliosis, joint contractures, and reduced bone mineral density.
Heart problems are reported in approximately 20% of CDG patients, encompassing issues like cardiomyopathies (thickening or weakening of the heart muscle), structural heart defects, and fluid accumulation around the heart (pericardial effusion). Endocrine issues, such as hypothyroidism, hypoglycemia, and delayed puberty, can also occur.
Diagnosing CDGs
Diagnosing CDG often begins when a person presents with a combination of unexplained symptoms affecting multiple body systems. Because CDGs are rare and their symptoms overlap with many other conditions, initial misdiagnosis with disorders like cerebral palsy can occur. A thorough evaluation includes reviewing the patient’s symptoms, developmental history, and family medical history.
Biochemical screening tests are a primary tool for identifying CDG. Transferrin isoelectric focusing (TIEF) is a widely used screening test that looks for abnormal glycosylation patterns of transferrin, a protein in the blood. This test can help determine if there is a defect in N-glycosylation and categorize it as Type I or Type II, based on the specific changes in transferrin. Abnormalities in other blood proteins, such as apolipoprotein C-III, can also be assessed.
Definitive diagnosis of a specific CDG subtype typically requires genetic testing. Whole exome sequencing (WES) is increasingly used as a comprehensive method to identify the underlying genetic mutation responsible for the glycosylation defect. This advanced sequencing technique examines the protein-coding regions of the genome, allowing for the identification of specific gene changes that cause CDG.
Managing CDGs
For most CDG types, there is currently no cure, so management focuses on addressing specific symptoms and improving overall quality of life. This often involves a multidisciplinary team approach, including various medical specialists, therapists, and dietitians. Comprehensive care aims to manage the diverse manifestations across affected body systems.
Treatment strategies are individualized based on the specific CDG type and the symptoms present. Dietary interventions can be beneficial for certain subtypes; for instance, mannose supplementation is an approved treatment for MPI-CDG, often leading to significant improvement in clinical signs, though liver involvement may persist.
Supportive therapies include physical, occupational, and speech therapy to address developmental delays and motor deficits. Medications are used to control seizures, manage heart problems like cardiomyopathy or pericardial effusions, and treat hormonal imbalances such as hypothyroidism. Orthopedic interventions, including surgery or mobility aids, may be necessary for skeletal abnormalities like scoliosis. Ongoing research continues to explore new therapeutic avenues, including gene therapies and other molecular approaches, to provide more targeted treatments and potential cures for CDGs.