Research

Research into Congenital Disorders of Glycosylation (CDG)

Why does CDG occur?

A Congenital Disorder means the disorder is present from birth.  Congenital Disorders of Glycosylation (CDG) is an inborn error of metabolism.  It is mostly a recessive hereditary genetic disorder. There are approximately 1000 diagnosed cases worldwide.

Glycosylation is the process in which sugar trees (glycans) are attached to proteins in a specific order. These are called glycoproteins and are vital for the development of healthy cells and, therefore, the body’s healthy growth and development.

The initial test for CDG is a blood test to look for abnormalities in the transferrin pattern.  Errors in the transferrin pattern results in a type I or type II CDG.

“The transferrin protein carries two ‘glyco’-trees, each having two branches in most of the cases.  In CDG type I, one or both of the trees are completely missing.  In CDG Type II, the base of the tree is present, but something happened to the branches” Mailys Guillard, Biomedical Engineer

Sugar ‘trees’ or ‘chains’ are very important for the proper function of the body’s proteins. Problems with the sugar trees (glycans) being absent or incomplete interferes with the proper function of the proteins.  Proper cell function, as well as good cell to cell communication, is very important, as it regulates the activity and function of enzymes, hormones, and proteins in the body.  This is needed for good health, growth and development. 

When there is an error in the glycosylation process, this can have serious consequences throughout the entire body.  Symptoms can range from mild to severe.  But CDG can significantly affect growth and development of the brain, as well as the development of speech, language, vision and hearing, and a failure to thrive (growth).   It can also affect organs such as heart, liver and kidneys.

PMM2 is the most well-known CDG.

SLC35A2-CDG is the first CDG to be discovered that is not inherited, but is a spontaneous mutation.

Testing for CDG

Transferrin testing does not always show as abnormal, so more specialist testing is required to either confirm or rule out CDG. 

Transferrin can also normalise over time.  Research has shown that normalisation in transferrin levels can miss a diagnosis for CDG.  Because Transferrin testing does not always show as abnormal, more specialist testing is required to either confirm or rule out CDG. The earlier testing for CDG is carried out, the better the chances of diagnosis.  The liver’s function can normalise over the years; which will affect the test results of the Isoelectric focussing of transferrin serum.  In these cases, further specialist testing is needed to either confirm or rule out a diagnosis of CDG.

“Type I and Type 2 classification is becoming a little more difficult now, because not all genes that should give a Type I or type II affect Transferrin.  While Transferrin is useful, it is not a guarantee to be abnormal.”  Bobby Ng, Sanford Burnham, 5 May 2017

Advances in the field of genetics shows that the discovery of new CDG is growing very rapidly.  It is expected that many different CDG will be discovered/detected in the future.

The important thing to remember is that if a child presents with symptoms such as developmental delay, organ failure and failure to thrive, then to suspect CDG.  Many tests are already available as standard to test for unexplained developmental delays in children.  There needs to be more awareness of CDG amongst the medical practitioners, so that testing for CDG happens too.

Research is vital to diagnosing CDG.  With the knowledge Sanford Burnham Medical Research Institute has gained through the discovery of three different CDG: SLC35A2-CDG, ALG13-CDG and SSR4-CDG, which are all spontaneous mutations, it is important that a combination of genetic and biochemical diagnoses are used.

Brain function is involved in most CDG.  Proper brain development is crucial early in foetal development.  CDG can affect the development of the brain and leave those affected by CDG with physical, neurological and learning difficulties, as well as medical complications involving the internal organs, such as heart, liver and kidneys.  Brain tissue does not repair itself like the liver cells can.  It is difficult to approach the brain with any treatment as brain development is already affected by the time an affected child is born. Impaired development of, or damage to the brain, cannot be reversed or treated.  Treatments may make the body healthy but you cannot, unfortunately, fix the brain if impaired development or damage is already evident.  Professor Jaak Jaeken refers to this as “sugar tragedies” in his video below:

The Future for CDG

Jaak Jaeken sums this up perfectly by saying:

  • More awareness and research!!!!
  • More collaboration between scientists, patients, politicians.
  • Better screening.
  • Better understanding.
  • Efficient treatments.
  • Courage and perseverance.

Is there a treatment for CDG?

PMM2-CDG (CDG-Ia)

The idea of Glycomine as a treatment for PMM2-CDG patients has recently been raised.  It is extremely important to remember that,

“The Glycomine idea is a worthy approach for PMM2; but it’s really years away from use.”

It is still in the very early stages of development and it will be years before it becomes a possibility.  However, this shows that research continues to give CDG patients and families hope.

MP1-CDG (CDG-Ib)

“Mannose looks good for these patients.”

SLC35A2-CDG (CDG-IIm)

“Galactose – Only one paper claims an effect and that is only on transferrin.  No clinical improvement.”

PGM1

“Galactose – there appears to be some benefit.  That looks good.”

Source: Pr.Hud Freeze, Director of the Human Genetics Program at Sanford Burnham Medical Research Institute, 14th June 2017


Let’s further CDG research together!


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