What Are Congenital Disorders of Glycosylation (CDG)?

Congenital disorders of glycosylation (CDG) is a term used to describe a group of more than 130 rare genetic, metabolic disorders. These disorders result from defects in the body's chemical process known as glycosylation. Normal glycosylation occurs when sugar-building blocks called glycans are added to the cells' proteins, such as enzymes, throughout the body. Adding glycans to enzymes is vital to the function of your cells. CDG occurs when there is a deficiency or a lack of enzymes.

CDG impacts multiple systems in the body, almost always causing neurological issues. CDG usually becomes apparent in infancy and can include a wide range of health issues caused by this chemical malfunction.

While the prevalence of all types of CDG is not well established, scientists in a 2018 study estimated that 1 in 10,000 European and African American people are impacted. This estimate is based on an individual's susceptibility or predisposition to 53 different known genes. To date, though, fewer than 100 cases have been reported for most versions of CDG.

Types of CDG

While there are more than 130 types of CDG, these disorders can be divided into four subdivisions. These subdivisions include: disorders of protein N-glycosylation, disorders of protein O-glycosylation, disorders of glycosphingolipid and GPI-anchor glycosylation, and disorders of multiple glycosylation and other pathways. The most frequently diagnosed group is N-glycosylation disorders.

Disorders of Protein N-Glycosylation

Most types of CDG are a form of N-glycosylation, which involve carbohydrates called N-linked glycans. This form of CDG is caused by an enzyme deficiency or other malfunction. The most common type of CDG is PMM2-CDG, which is a form of N-glycosylation. 

Disorder of Protein O-Glycosylation

These disorders are caused by an enzyme deficiency or other malfunction somewhere along the O-glycosylation pathway. Some of the disorders in this subdivision are more well-known and have more familiar names. For instance, some forms of muscular dystrophy fall into this category.

Disorders of Glycosphingolipid and GPI-Anchor Glycosylation

Disorders in this subdivision involve defects in the glycosylation of two types of lipid-containing molecules: glycosphingolipids (GSL) and glycosylphosphatidylinositol (GPI) anchors. Glycolipids are responsible for a wide range of bodily functions; therefore, types of CDG associated with a defect in their production can be expressed in many different ways.

Disorders of Multiple Glycosylation and Other Pathways

Sometimes CDG occurs when defects affect and change multiple glycosylation pathways. For instance, a person can have defects that affect both N-linked and O-linked glycosylation pathways.

CDG Symptoms

Because CDG encompasses so many different disorders, the symptoms can vary in severity even among people with the same diagnosis or from the same family. Yet, despite this wide variety of symptoms, most people with CDG will have neurological symptoms impacting their brain, spine, or both. They also might experience diminished muscle tone, developmental disabilities, cognitive impairment, and an underdeveloped cerebellum (the part of the brain that controls balance and posture).

Researchers have also found that some people may have kidney, liver, and skeletal system abnormalities as well as fluid around their lungs and heart. In fact, about 20% of people with CDG have heart disease—primarily cardiomyopathy, arrhythmias, pericardial effusion, and structural abnormalities. People with CDG also may experience scaly skin or rashes, immunodeficiencies, hypoglycemia, and growth delays. Some may even have stroke-like episodes or seizures.

Other common symptoms can include:

• Abnormal fat distribution
• Bleeding or blood clotting issues 
• Vomiting and diarrhea
• Crossed eyes (strabismus)
• Distinctive facial features 
• Feeding difficulties and failure to thrive, meaning they cannot gain enough weight

Causes

Because CDG is a group of different genetic disorders, a child usually inherits it from their parents. Most of the time, that inheritance occurs when both parents carry the genetic mutation for a form of CDG but do not have symptoms themselves. When this occurs, it is called an autosomal recessive pattern.

Meanwhile, other forms of CDG can be inherited from either parent, which makes them autosomal dominant conditions. This means that only one parent needs to have a copy of the abnormal gene for the child to develop the condition.

It also is possible that the gene mutations that lead to CDG are not inherited at all. Instead, they are new, random mutations.  

Risk Factors

If both parents have the abnormal gene, there is a 25% chance with each pregnancy that they will have a child with CDG. Meanwhile, the risk of having a child who is a carrier like their parents is 50% with each pregnancy. And the likelihood that a child will have unaffected genes from both parents is 25%.

If a parent has a dominant form of CDG, the risk of passing it on to a child is 50% for each pregnancy, regardless of the sex of the parent or child. But, if a child has a new, random mutation that is not carried by either parent, their siblings are much less likely to develop the disease.

Diagnosis

Because the symptoms of CDG can be confused with other conditions, people with CDG are often misdiagnosed with unrelated conditions such as cerebral palsy or other genetic disorders. But experts in CDG insist that any time a person has symptoms that impact multiple systems in the body, CDG should be considered.

If a healthcare provider suspects CDG, they will look at the person's medical history and perform a thorough evaluation. Then, they will order some specialized tests such as:

• Blood test: Some forms of CDG can be identified with a simple blood test that looks for abnormal glycoprotein levels, or total levels of glycans attached to proteins (such as transferrin).
• Mass spectrometry: This blood test also may be used to detect abnormal transferrin and can sometimes be used to narrow down or confirm suspected defects.
• Genetic testing: Molecular genetic testing is used to confirm CDG and identify the specific form.

Treatments for CDG  

There is no cure for CDG. However, there are treatments available to manage symptoms and improve quality of life. Each person's treatment plan will be unique and is based on their symptoms and the severity of those symptoms. Here are some potential treatments people with CDG may undergo:

• Nutritional interventions: Sometimes people with CDG will undergo feeding therapy for growth or eating problems, which could include special infant formula for a baby. There also is the option of thickening liquid foods or using a nasogastric tube (feeding tube).
• Heart monitoring: If a heart problem is found or suspected, the person may receive regular screening for fluid around the heart or thickening and stiffness of the heart muscle. If any of these conditions are found, they may be treated with medication, surgery, or fluid drainage.
• Liver monitoring: If there is a risk of liver failure, regular liver monitoring is usually recommended. The person also may receive albumin infusions and vitamin K supplementation when warranted.
• Thyroid treatment: Sometimes a person with CDG will have low levels of free thyroxine, so they will need to be treated for an underactive thyroid gland (hypothyroidism).
• Sugar therapy: People who have a sugar-responsive type of CDG will sometimes undergo a rare sugar therapy (with mannose or galactose).
• Vision correction: If a person has vision issues such as crossed eyes, they may receive patching, glasses, or corrective surgery.
• Therapy: For people who have developmental delays, early intervention with occupational, speech, and physical therapy may be recommended, and is sometimes ongoing. Vocational training also may be offered to help develop work and life skills.
• Medications: If a person with CDG has blood clotting issues, they may be treated with blood thinners or plasma infusions, while people who experience seizures may be given anti-epileptic medication. In some cases, epilepsy surgery may be recommended.
  

There also is the option to participate in clinical trials, which sometimes provides the opportunity to try experimental treatments. If interested, talk to a healthcare provider about this option. Or, visit the National Organization of Rare Disorders website or call them toll-free at 1-800-411-1222.

Prevention

Because CDG is a genetic disorder, it is not possible to prevent it from occurring, especially if the type of CDG that occurs is a random mutation, or you and your partner are not aware that you have one of the gene mutations. That said, if you are concerned that your child may develop CDG, there is genetic screening available to see if you have one of 54 different gene mutations.

But because there are more than 130 variations—and potentially more that have not been identified—this path is not a 100% reliable method of identifying all possible types of CDG. However, if you do have the screening and one of the mutations is identified, a healthcare provider can discuss your options with you.

Related Conditions

When a person has CDG, it can potentially impact multiple systems in their body. Consequently, there are a number of related conditions that can occur alongside this condition—all of which are caused by defects in the body's chemical process known as glycosylation. Here is an overview of some of the common conditions that are related to CDG:

• Ataxia: Ataxia, or the loss of one's ability to control their movements, occurs in people with CDG as a result of brain disease. It can cause a lack of coordination, poor body posture, difficulty speaking and problems with swallowing. 
• Epilepsy and seizures: People with CDG frequently have a seizure or develop epilepsy alongside their condition.
• Peripheral neuropathy: When someone has CDG is not uncommon for them to have issues with their peripheral nerves, which can reduce muscle strength and difficulties in walking. 
• Hypoplasia: People with CDG—especially those with PMM2-CDG—experience a defect in the formation of their cerebellum, which leaves it small and poorly developed.
• Retinitis pigmentosa: A person with CDG can experience degeneration of their retina and loss of vision. Scientists speculate that those with CDG are experiencing a glycosylation defect within parts of their retina. 
• Pericardial effusion: This heart condition, which involves extra fluid around the heart, is common in individuals with some types of CDG. 
  
• Hypothyroidism: Many people with CDG experience issues with their body creating too few thyroid hormones.

Living With CDG  

If you have a child or family member diagnosed with CDG, it is important to know that while their condition is rare, you are not alone. In fact, one of the first things you should do after a diagnosis is join the CDG CARE Family Support Network.

This group was created by families who wanted to know more about CDG and has evolved into an organization designed help families connect. Additionally, you will find information about programs and services designed to help people with CDG build strengths and meet challenges from early childhood through adulthood.