Professor Jaak Jaeken | An overview of the discovery and complexity of congenital disorders of glycosylation (CDG)
Q. Can you explain to us what CDG is and what makes it so complex?
About half of our body proteins and many lipids carry a complex ‘sugar tree’ called glycan. This glycan consists of several branches, composed of different sugars, or monosaccharides, such as mannose, galactose, sialic acid and others. The assembly, or the building, of the glycan and the attachment to the protein and the lipids is called glycosylation. The glycan is very important for the many different functions of the proteins and the lipids carrying these glycans.
In CDG, there is a genetic defect in the glycan assembly, and more specifically, in the enzymes and transporters needed for this assembly. There are several hundreds of these enzymes and transporters known, and we know defects in some 160 of them.
Glycosylation is present in all our organs and systems, particularly in the brain. Therefore, these patients show mostly multisystem involvement, including brain disease, with intellectual disability, epilepsy, hypertonia, and ataxia, and symptoms from other organs such as the liver, eyes, kidneys, heart, immunological system and many others. A few CDG involve only one organ because of a defect in the glycosylation that is specific for that organ.
The nomenclature of CDG has been changed over time. Initially, I numbered the CDG in the order of discovery. We had CDG-Ia, CDG-Ib, etcetera, until we were at the end of the alphabet, and then CDG-IIa, CDG-IIb, and so on. However, in 2009 we decided to introduce a more informative nomenclature by using the gene name followed by the umbrella name CDG. For example, PMM2-CDG. PMM-2 stands for phosphomannomutase 2, and this is still the most frequent CDG, with nearly 1000 reported patients. As to the other CDG, only between 1 and 100 patients have been reported.
Q. Could you tell us about the history of CDG and your work?
This story started in 1978 when I was asked to investigate 18-month-old twin sisters because of their psychomotor disability. This meant they were unable to speak and could not sit without support. I started the usual investigations of blood and urine and found a combination of protein abnormalities that I had not observed before. I was of course curious to know the mechanism, or the cause, of these findings. It took me some time to arrive at the conclusion that there should be a problem with something that is common to these proteins. By looking into the literature, I came across a paper from Professor Henk van Eijk, a blood specialist in Rotterdam, about transferrin isoelectric focusing.
Isoelectric focusing is a technique of electrophoresis (the movement of charged particles in a fluid or gel under the influence of an electric field) in which the resolution is improved by maintaining a pH gradient between the electrodes (definitions from Oxford Languages).
Transferrin is a protein that transports iron in the blood, and when this protein is subjected to an electric field, it shows several bands. The most important band is called 4-sialotransferrin, because it carries 4 sialic acid molecules. Sialic acid is a sugar with a negative electric charge. When there is a change in the sialic acid content, there is also a change in the pattern of these bands on the isoelectric focusing. I thought that this test might be useful to clarify the problem of my two patients, and so I sent serum to Professor Van Eijk. Within two days, the professor found an abnormality that he had never seen before—a decrease in the sugar sialic acid in transferrin. Subsequently, we found that many other proteins showed the same deficiency in sialic acid. This was the start of the CDG story. Many scientists have since then contributed to the unravelling of the CDG fields, and I hereby want to mention in particular geneticist Professor Gert Matthijs and biochemist Professor Emile van Schaftingen.
PMM2-CDG is by far the most frequent CDG. The start was very slow but the discovery of other CDG was more rapid with sometimes more than 10 CDG discovered in one year. Actually, there are many research groups all over the world working on CDG with advanced genetic and other techniques, and so the discoveries continue to be much more rapid.
Q. What have been your biggest challenges in treating patients with CDG over your career?
The biggest challenge in treating patients with CDG is the lack of effective treatments. There is a more or less effective treatment for only two CDG. One is an oral treatment with the sugar mannose, and the other is a treatment with oral uridine. Partial treatments are available with two other sugars, namely galactose and fructose, but promisingly, other treatments are in the pipeline with clinical trials in different phases.
Q. In your opinion, what is the biggest unmet need for those with CDG?
A big unmet need for these patients, besides the lack of effective treatment, is the lack of awareness of these diseases by physicians. This can lead to great delays in diagnosis, sometimes for many years. Some patients have seen up to 20 doctors before arriving at the diagnosis.
Q. Looking to the future, what are your hopes for research and treatment development for CDG?
I have many hopes for CDG diagnostics and treatment in the future. Firstly, that unknown CDG are discovered as soon as possible—it is likely there are still 100 or more still to be discovered. Secondly, that patients are diagnosed very early, preferably in the neonatal period (first four weeks of a child’s life)—hence the importance of neonatal screening. Finally, that effective treatments become available with minimum side effects and that patients would receive an optimal symptomatic treatment by a dedicated multidisciplinary team. Optimal psychological and emotional support for individuals living with CDG and their families should also be a high priority for the CDG community.
For more information and support around CDG please go to:
Jaeken J, Van Eijk HG, van der Heul C et al. Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly diagnosed genetic syndrome. Clin Chim Acta 1984; 144: 245-247
Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett 1995; 377: 318-320
Matthijs G, Schollen E, Pardon E et al. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet 1997; 16: 88-92
Jaeken J, Péanne R. What is new in CDG? J Inherit Metab Dis 2017; 40: 569-586
Brasil S, Pascoal C, Francisco R et al. CDG therapies: from bench to bedside. In J Mol Sci 2018; 19: 1304. doi: 10.3390/ijms19051304
Rare Revolution Editor