Rare Epilepsy Syndromes. Motivated by a recent paper in JIMD Reports, I wanted to use this post to present a very rare group of disorders, in which glycosylation of a variety of tissue proteins and/or lipids is deficient. These so-called congenital disorders of glycosylation (CDG) are a highly heterogeneous group of recessive disorders that you might be confronted with. As CDG may masquerade as otherwise non-specific epileptic encephalopathies, you might encounter them clinically or by browsing through exomes of patients with RES. Imtiaz and colleagues now report on two brothers in a large Saudi family with 18 affected siblings. They identified a mutation in DPAGT1, which is known to cause CDG Ij.
To be excluded. I have never met a patient with CDG, but we have excluded the diagnosis in many. This is probably the experience that most of you who see patients share. The CDGs are extremely rare disorders that are on the differential list in children with epileptic encephalopathy, muscular hypotonia and primary developmental delay. The diagnosis can usually be excluded by HPLC or isoelectric focusing of transferrin (which is a test that you can send off and don’t have to bother to understand it because it usually comes back negative). The CDGs are considered metabolic disorders and often treated in specialized centers.
Pathomechanisms. Many if not most of our surface proteins are not only made of amino acids, but also carry oligosaccharide or polysaccharide residues. In brief, these sugar residues modify and diversify the surface of many proteins and are involved in a wide range of cellular processes. The assembly of these sugar residues is not random, but tightly regulated and orchestrated. Accordingly, a large number of enzymes are involved in putting together the “sugar coating” of a protein. This complexity is reflected in wide range enzymatic defects that lead to disease. The congenital disorders of glycosylation comprise more than 40 recessive disorders. In brief, type I CDGs affect the assembly and type II the processing of the so-called glycan moieties. Even for the most common subtype (CDG Ia), not more than 500 patients have been reported in the literature; for many of the rarer CDGs, probably fewer than 10 patients are known. Therefore, limited knowledge exists regarding the phenotypic spectrum. Usually, you would think of CDGs as multisystem diseases, also affecting coagulation or liver function and combined with dysmorphic features such as fat pads or inverted nipples. However, these additional features might be absent.
DPAGT1 and CDG Ij. In the case report by Imtiaz and colleagues, both brothers show a severe primary developmental delay, muscular hypotonia and relatively easy to treat unclassified epilepsy with an EEG characterized by multifocal discharges. Dysmorphic features were absent and a large panel of investigations was performed including biochemical analysis of transferrin, which was abnormal. Suggesting a CDG, they performed linkage and eventually zeroed in on the DPAGT1 gene, which has previously been described to cause CDG Ij. DPAGT1 codes for the enzyme UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (you don’t have to remember that). In summary, in order for the glycans to be constructed, they are first attached to dolichol as a membrane anchor. This first step is catalyzed by DPAGT1 and deficient in CDG Ij.
Lessons for RES. None of the RES trios analyzed so far has a mutation in the CDG genes and it is an open question what percentage of the epileptic encephalopathies are hidden neurometabolic disorders. In the case of the family reported by Imtiaz and colleagues, patients from a consanguineous family were analyzed, which greatly increases the risk of a recessive disease. However, for the epileptic encephalopathies at large, the question remains open regarding the role of recessive mutations. The CDGs, however, are one group of disorders that will be repeatedly discussed with increasing genetic information obtained from patients with epileptic encephalopathies, be it causative variation or genomic noise.