Diagnostic innovations for the Congenital Disorders of Glycosylation
Written by Dr. Dirk Lefeber, published 8 months ago.
Fast and accurate diagnosis of metabolic diseases is very important to provide the best care for patients. Fortunately, a good screening assay is available for CDG, which allows rapid detection of a defect in the glycosylation of proteins. This screening assay is based on the analysis of the differently glycosylated forms of the protein transferrin in patient serum. In the screening stage, it is very important to exclude the possibility of a secondary cause of abnormal glycosylation.
After exclusion of secondary causes, it still can be a major challenge to identify the specific CDG subtype. As known, the major subtype CDG-Ia (PMM2-CDG) can quickly be diagnosed using an enzyme assay in leukocytes or patient fibroblasts. Progress in CDG research in the last decade has educated us how to use specific clinical symptoms to find the underlying genetic defect. However, in many cases, gene identification is a time consuming track up to years and still many patients await their definitive diagnosis. Therefore, innovative techniques are needed.
High-resolution mass spectrometry
After a positive CDG screening result, detailed knowledge of the glycan structures on transferrin and other proteins and even the lipid dolichol can help to find the gene defect. Mass spectrometry is a chemical tool to analyse the “weight” of glycans. In CDG, the structure of glycans, and thereby their weight is abnormal, which can be analysed in detail by mass spectrometry. Depending on the position of the genetic defect in the N-glycosylation pathway, the glycan structures are different and thereby provide a kind of fingerprint for a certain CDG subtype. Still novel and more accessible methods are needed to speed up this phase of the diagnostic track.
Next-generation sequencing
The last decade has seen a revolution of techniques to detect disease-causing mutations in our DNA. These so-called next-generation sequencing techniques allow the parallel analysis of large amounts of our genome in short periods of time. Instead of the current situation, where for example 30 potential CDG genes have to be analysed individually, more than 20.000 genes are analysed in parallel within a couple of months, including all known and potentially new CDG genes. In this way, we have already been able to find several novel CDG-I gene defects and solve >95% of the defects in CDG-I patients.
In conclusion, innovative methods are on the horizon to be implemented in CDG diagnostics, and, if sufficient additional research budgets are available, will help to reach a final diagnosis within 3 months after identification of a CDG.
Dr. Dirk Lefeber
Written by Dr. Dirk Lefeber, published 8 months ago.
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