What Is CDG Disease? Symptoms, Causes, and Treatment

Congenital disorders of glycosylation (CDG) are a large group of rare inherited conditions, present from birth, in which the body’s sugar-tagging of proteins goes wrong.¹ Nearly every organ relies on correctly tagged proteins, so CDG usually affects many body systems at once, with the brain most often involved.² The outlook depends heavily on which type a child has: a few types can be treated with a simple sugar taken by mouth, while most are managed symptom by symptom.³

What Goes Wrong in the Body With CDG

Glycosylation is the process of building sugar chains and attaching them to proteins and fats inside cells. These chains work as tags. They help a new protein fold into its correct shape before it leaves the cell’s protein-making area.⁴ Cells check the tags, and proteins that fail the check are broken down instead of being sent out.⁵ Other tags keep certain proteins in place until they are correctly finished.⁶ When tagging fails, many proteins come out misshapen, missing or not working, which is why so many organs can be affected.

More than 130 types of CDG have been identified since the first was described in 1980.⁷ Each type is now named after the faulty gene followed by “-CDG,” so the old “CDG type 1a” is now PMM2-CDG.⁸ Types are also grouped by which tagging pathway breaks, and the most common group affects the tags added early, as proteins are made.⁹ PMM2-CDG accounts for about 6 in 10 of all CDG cases and blocks an essential early step of tagging.¹⁰

Older reports, or some doctors, may still say “type Ia” or “type Ib” for the same conditions. Knowing the exact type matters because treatment options differ from one type to the next.

Common Symptoms of CDG

The most common signs across CDG types are poor growth, developmental delay, unusual facial features, and changes in blood clotting and hormones.¹¹ The liver, hormone glands, blood and brain are often affected together.¹² A few people with PMM2-CDG have a much milder picture, with only an underdeveloped balance centre of the brain.¹³

At home, parents of babies and toddlers often first notice feeding trouble, poor weight gain, and low muscle tone (a floppy feel when held), alongside slow milestones. Some children also have unusual fat pads or inverted nipples, or eyes that turn inward or move abnormally, though not all do. None of these signs alone points to CDG, since each has many other causes. It is the combination across several body systems that makes doctors consider it.

Brain and nerve symptoms are the most common. Across CDG types, frequent problems include epilepsy, intellectual disability, muscle weakness, nerve damage and stroke-like episodes.¹⁴ In PMM2-CDG, about 9 in 10 children have poor balance and coordination and about 8 in 10 have muscle weakness.¹⁵ More than half have seizures, and about half have nerve damage in the limbs.¹⁶ About 1 in 4 have involuntary movements such as twisting or jerking, and about 1 in 6 have stroke-like episodes.¹⁷

A stroke-like episode often looks like a stroke: sudden weakness on one side of the body, sometimes with a headache. It can come with seizures and may fluctuate over hours or days. The weakness often improves over time. Even so, any sudden weakness needs urgent medical care, because a real clot or bleed is also possible.

Brain scans in PMM2-CDG usually show shrinking of the balance centre of the brain and the brainstem.¹⁸ Some scans in the first years of life are normal, though.¹⁹ In children whose early scans show slow development of the brain’s insulation, later scans usually show it catching up.²⁰

The same type can range from mild balance problems to severe illness in infancy. The exact gene changes a child carries influence severity, so siblings or other families with the same type may not predict your child’s course.

What Causes CDG and How It Is Inherited

Almost all CDG types are autosomal recessive, meaning a child inherits one faulty copy of the gene from each parent.²¹ A carrier has one working copy and one faulty copy, and the working copy usually makes enough of the protein to keep them well. That is why parents are usually healthy carriers who did not know they carried the change, and why two healthy parents can have a child with CDG with no family history.

A child is affected only when both copies are faulty. Each pregnancy of the same two carrier parents has a 1 in 4 chance of an affected child. The chance applies separately to each pregnancy. A few types are inherited differently: in one SSR4-CDG patient, the change came from his mother alone.²²

Nothing done during pregnancy causes CDG, and carrying a single faulty copy is common and harmless. Genetic counselling can explain testing for future pregnancies and for relatives. Once the child’s gene changes are known, relatives can be tested for those exact changes, usually from a simple blood or saliva sample.

PMM2-CDG is the most often reported type, followed by types including FKTN-CDG, EXT1/EXT2-CDG, ALG6-CDG and PIGA-CDG.²³ PMM2-CDG is estimated to affect about 1 in 20,000 Ashkenazi Jewish, 1 in 27,000 European and 1 in 64,000 mixed-ancestry American people.²⁴ All other types in its group are much rarer.²⁵

How CDG Is Diagnosed

The path usually starts when a doctor notices delay, poor growth or balance problems along with issues in other organs. A blood screen comes next. It usually checks transferrin, a blood protein, to see whether its sugar tags are incomplete.²⁶ A more detailed analysis of the transferrin tags can point toward specific types.²⁷

The transferrin blood test needs only a small blood sample, drawn like any routine blood test, so no special preparation is usually needed. The result shows whether transferrin carries too few sugar tags, and the pattern of missing tags helps indicate the group of CDG. Some sample-handling issues and other conditions, such as certain liver problems, can also change the pattern, so doctors read the result alongside the child’s symptoms. A normal screen doesn’t always rule CDG out, since PMM2-CDG has been found in people with normal routine screening.²⁸

If the screen is abnormal, genetic testing identifies the gene and type. Gene panels that test many CDG genes at once can detect the known gene changes reliably.²⁹ Still, in one lab’s testing, only about 15% of children referred for CDG gene tests got a genetic diagnosis.³⁰ Wider testing of all genes can find the cause when panels don’t, including newly recognized types.³¹

Some gene changes are first reported as “uncertain significance,” meaning the lab can’t yet say whether the change causes disease. That is not a diagnosis and not a rule-out. Such changes may later be confirmed by repeat tag tests and extra lab work.³² It is worth asking whether extra tests or family testing could clarify the result, and results can be reclassified later, so keep in touch with the genetics team.

Treatment Options for CDG

MPI-CDG can be fatal untreated but is readily treatable with mannose, a simple sugar taken by mouth.³³ Cells take in mannose directly and use it to bypass the broken step.³⁴ It improves or normalizes gut, hormone and clotting problems, with clotting often normal within weeks.³⁵ The usual dose is 150 to 170 mg per kg of body weight, four to five times a day.³⁶ Treatment must be lifelong, and missed doses have brought back diarrhea, clots and abnormal blood tests.³⁷ Because the dose is set by body weight and tracked with blood tests, mannose should be given only under medical supervision for a confirmed MPI-CDG diagnosis.

Sugar supplements don’t work for every type because the location of the block matters. Mannose works in MPI-CDG because the block comes before a step cells can skip. In PMM2-CDG the block sits where extra mannose can’t get around it.

Galactose, another simple sugar, improved liver function, hormone problems and low blood sugar episodes in PGM1-CDG, with no side effects seen.³⁸ In SLC35A2-CDG, 18 weeks of galactose improved growth and development in most children, and some had fewer seizures.³⁹ Evidence for other types such as SLC39A8-CDG and TMEM165-CDG comes from single cases or small groups.⁴⁰

No approved drug yet treats PMM2-CDG itself. Epalrestat, a diabetes nerve-pain drug approved in some Asian countries, raised enzyme activity and improved appetite and weight in one child.⁴¹ It is now in a larger clinical trial for children with PMM2-CDG.⁴² Govorestat, a related once-daily drug, has been tried in a single patient.⁴³ ClinicalTrials.gov lists active CDG trials by type. Single-patient results are encouraging but not proof.

Meanwhile, most care treats specific symptoms. For stroke-like episodes, doctors use brain scans, brainwave tests and clotting tests to choose between blood thinners, clotting factor replacement and seizure medicines.⁴⁴ Seizure medicines such as lorazepam or midazolam seem to help these episodes.⁴⁵ Aspirin, often used to prevent them, has no proven benefit and adds bleeding risk.⁴⁶ Surgery, long bed rest or hormone therapy need planning to prevent both bleeding and clots.⁴⁷

Life With CDG From Childhood to Adulthood

Adults with CDG commonly have intellectual disability, speech difficulty and unsteady walking.⁴⁸ After puberty, symptoms may stop progressing, and some people lead socially functional lives.⁴⁹ In PMM2-CDG, though, nerve damage, curving of the spine, clots and vision loss can keep progressing.⁵⁰ Brain scans show the balance centre keeps shrinking through childhood.⁵¹

Four adults with PMM2-CDG aged 19 to 36 were active and able to hold conversations despite moderate learning disability.⁵² They used wheelchairs and had spine curvature, thin bones and a retinal eye disease.⁵³ Seizures became occasional, and none had stroke-like episodes after their teens.⁵⁴ Puberty hormones were often lacking, so women didn’t menstruate.⁵⁵ Reports of adult life come from people who survived childhood, so they show what is possible and not what every child will experience.

For the teen years, regular eye, spine and nerve checks catch changes early, and hormone problems may need treatment at puberty. It helps to plan the move from children’s to adult care early. Adult doctors may be unfamiliar with CDG, so carry a summary of your child’s diagnosis and care.

Care Team and Support for Families

PMM2-CDG care requires a team of specialists, guided by international guidelines checking each organ system.⁵⁶ A metabolic or genetics specialist usually coordinates it. Neurology, physiotherapy, eye, hormone and blood specialists are often involved, and therapies for speech, movement and feeding support development. Problems with daily activities and behaviour limit independence and affect the whole family’s quality of life.⁵⁷ A written care plan, including clotting cautions for surgery, keeps everyone on the same page.

Day to day, families often juggle frequent appointments with several specialists, so a single coordinator or nurse contact can save a great deal of time. Therapy exercises, medicines and feeding routines usually fit into the home day, so parents become part of the treatment team. Illness, fever or poor feeding can worsen symptoms in some children, so many families keep a plan for when to call the team.

Parents describe receiving the diagnosis as exhausting and emotional, often meeting doctors who know little about CDG.⁵⁸ Long waits for diagnosis and few treatments add to distress.⁵⁹ Patient associations give families information, practical help and social support.⁶⁰ CDG Hub, CDG Care, the World CDG Organization and ClinicalTrials.gov share research and care information.⁶¹