Since Prof. Jaak Jaeken and colleagues first described the congenital disorders of glycosylation (CDGs) in 1980, more than 140 types were identified so far.^1),(2 And, while probably there are not as many CDGs as there are stars in the sky, this family of diseases has become vast and somehow difficult to grasp. Even so, their exact prevalence has yet to be established.

As Mendes et al. reviewed in the previous issue of this journal, CDGs are a group of genetic diseases, usually multisystem, both phenotypically and genotypically heterogeneous, and typically classified in four categories: N-glycosylation defects, O-glycosylation defects, combined glycosylation defects, and glycosphingolipid and glycosylphosphatidylinositol (GPI) anchor synthesis defects.² Most CDGs are autosomal recessive diseases, but some show an autosomal dominant or X-linked inheritance.

The multisystem manifestations of CDGs can be explained by the importance of N-glycosylation, O-glycosylation and GPI anchor biosynthesis pathways. As Mendes et al. explained further in their review, protein and lipid glycosylation is ubiquitous and physiologically essential.²

Almost all CDGs have neurological manifestations. Other features include abnormal fat distribution, connective tissue involvement, liver disease, coagulopathy, hyperinsulinemic hypoglycemia, cardiomyopathy, skeletal dysplasia, and immunodeficiency. Giving the wide phenotypic spectrum and the myriad of symptoms reported, CDG should be suspected in all patients with unexplained clinical history, namely those with multisystem manifestations.

Serum transferrin isoelectric focusing should be the first step in screening, but neither a positive test can confirm the diagnosis nor does a negative test exclude it. Still, it is an important phenotypic tool.

As stated by Mendes et al., genetic testing is the most specific diagnostic test.² Moreover, as next-generation sequencing is becoming widely available, diagnostic analysis is shifting from the classic “phenotype-to-genotype” to a “genotype-to-phenotype” / “reverse phenotyping” approach. Nevertheless (and this is worth mentioning), in spite of our supposedly finite genome, exome sequencing alone is continuously “spreading” variants of unknown significance, from the laboratory to the Metabolic Units and Medical Genetics services. An uphill challenge.

Fortunately, the diagnostic endeavor is increasingly paying off. For now, only a few types of CDG have a specific treatment but that is changing (although not as rapidly as we wish). Mannose-1-phosphate substrate replacement therapy is currently being investigated for PMM2-CDG treatment. Pharmacological chaperones are also a promising option. Gene therapy is probably the future (still mostly in the future). Perhaps the combination of treatments would be a potential solution (as already suggested for other inborn errors of metabolism).

A correct etiological diagnosis also allows a proper genetic counselling and disease or carrier status can be assessed in relatives at-risk. If the particular CDG is an autosomal recessive condition, the partners of carriers can also be screened for pathogenic variants in the specific gene, thus allowing the couple to know the risk of disease in their offspring. Pre-implantation genetic testing (PGT) and prenatal diagnosis are technically possible, but access may be difficult, especially to PGT.

Since long-term prognosis is difficult to predict, these CDG patients need a life-long multidisciplinary follow-up. Despite this support, morbidity and mortality are high.

It should also be noted that even access to diagnosis and treatment is commonly unequal and has several limitations. It is up to medical societies, scientists and patient groups to advocate for better knowledge and funding and for strengthening collaboration. In this aspect, awareness is key.