Congenital Disorders of Glycosylation (CDG) Forms

As specific forms of CDG are identified by researchers, they are grouped by the chemical and enzyme functions they affect, and named for the gene on which the mutation is found (PMM2-CDG, for example).

The genetic naming convention is relatively new, so CDG forms are sometimes still labelled by an earlier naming system which divided the forms into two broad groups (type I and type II) based on characteristics found in blood tests, with a lowercase letter indicating the order in which the forms were identified by researchers (CDG-Ia, for example, is the former name for PMM2-CDG). Confusing matters a bit more, the older naming convention is still used to identify some forms of CDG in patients after blood tests are used to detect the disorder and before genetic testing confirms a specific genetic diagnosis. Over time, the older naming convention is expected to disappear.

The most common forms of CDG, and the greatest number of forms, are those that affect N-glycosylation, the process of forming sugar building blocks (glycans) from carbohydrates called oligosaccharides and attaching them to proteins. These forms are classified as N-linked CDG, and divided into type I and type II based on patterns of glycans and their attachment to proteins as detected in blood tests.

N-linked type I forms of CDG have genetic defects that prevent the oligosaccharide building blocks from attaching to proteins as new proteins are formed. N-linked type I forms of CDG include (among many others):

• PMM2-CDG – The most common type of CDG, formerly known as CDG-Ia. PMM2-CDG can present with a wide variety of symptoms and with a wide range of severity.
• MPI-CDG – Symptoms may include very low blood sugar, scarring of the liver and failure to thrive. Formerly known as CDG-Ib.
• GMPPA-CDG – Symptoms may include feeding difficulties and gastrointestinal defects.
• PGM1-CDG – Symptoms may include muscle weakness, short stature, cleft palate, blood clotting problems and liver disease.

N-linked type II forms of CDG have genetic defects that affect the trimming or remodeling of oligosaccharide building blocks once they are attached to proteins. N-linked type II forms of CDG include:

• MAN1B1-CDG – Symptoms may include intellectual disability, facial anomalies and behavior issues.
• MGAT2-CDG – Symptoms may include seizures, intellectual and motor disabilities, facial anomalies and behavior issues.

O-linked forms of CDG typically produce a more limited set of medical issues, affecting only one or a few body systems. O-linked forms of CDG include:

• EXT1/EXT2-CDG – Symptoms may include bony growths or tumors on the ends of the long bones of the legs, arms, fingers and toes. Also known as hereditary multiple exostoses.
• B4GALT7-CDG – Symptoms may include the appearance of premature aging, loose skin, loose joints and an abnormally small head (microcephaly).
• B3GALTL-CDG – Symptoms may include eye problems, developmental delays, facial anomalies and short stature.

N- and O-linked forms of CDG affect the trimming or remodeling of  sugar building blocks in the Golgi apparatus, a part of the cell that modifies and sorts proteins for secretion. N- and O-linked forms of CDG include:

• DPM1-CDG – Symptoms may include seizures, developmental delays and vision problems.
• DOLK-CDG – Symptoms may include seizures, low muscle tone or floppiness (hypotonia), abnormally small head (microcephaly), scaly skin and failure to thrive.

CDG due to GPI-anchor synthesis defects affect the creation of glycosylphosphatidylinositol (GPI) anchors, which work to attach specific proteins to cells. Forms of GDG due to GPI-anchor synthesis defects include:

• PIGN-CDG – Symptoms may include seizures, low muscle tone or floppiness (hypotonia), developmental delays, problems with eye movement and facial and internal anomalies.
• PIGV-CDG – Symptoms may include seizures, cognitive impairment and facial and skeletal anomalies. Also known as Mabry syndrome.

CDG due to glycosaminoglycan (GAG) synthesis defects affect the creation of GAGs — repeating patterns of different sugars that form structures for connective tissue. GAG synthesis defects may cause problems in bones, cartilage, ligaments, skin and eyes.