Electroclinical Features of Early-Onset Epileptic Encephalopathies in Congenital Disorders of Glycosylation (CDGs)

Abstract

Congenital disorders of glycosylation (CDG) are a constantly growing group of genetic defects of glycoprotein and glycolipid glycan synthesis. CDGs are usually multisystem diseases, and in the majority of patients, there is an important neurological involvement comprising psychomotor disability, hypotonia, ataxia, seizures, stroke-like episodes, and peripheral neuropathy. To assess the incidence, among early-onset epileptic encephalopathies (EOEE), of patients with identified congenital disorders of glycosylation (CDG), we made a review of clinical, electrophysiological, and neuroimaging findings of 27 CDG patients focusing on seizure onset, semiology and frequency, response to antiepileptic drugs (AED), and early epileptic manifestations. Epilepsy was uncommon in PMM2-CDG (11%), while it was a main concern in other rare forms. We describe a series of patients with EOEE and genetically confirmed CDG (ALG3-CDG, ALG6-CDG, DPM2-CDG, ALG1-CDG). Epileptic seizures at onset included myoclonic and clonic fits and focal seizures. With time, patients developed recurrent and intractable seizures principally tonic-clonic seizures, infantile spasms, and myoclonic seizures. Electrophysiological correlates included focal and multifocal epileptic discharges, slowed background rhythm, and generalized epileptic activity including burst suppression pattern and status epilepticus. We propose a diagnostic flowchart for the early diagnosis of CDG in patients presenting with EOEE and suggest to perform serum transferrin IEF (or capillary zone electrophoresis) as a first-line screening in early-onset epilepsy.

Epileptic spasms in congenital disorders of glycosylation

“…We report five children presenting epileptic spasms without hypsarrhythmia associated with various CDG syndromes. Despite the fact that epilepsy is one of the main neurological features described in CDG patients, detailed characterization of ictal semiology and neurophysiological patterns is rare (de Lonlay et al ., ; Morava et al ., ; Clayton and Grunewald, ; Dupré et al ., ; Jaeken, ; Freeze et al ., ; Funke et al ., ; Fiumara et al , ), and epileptic spasms without hypsarrhythmia associated with myoclonus have not yet been reported.…”

“…Severe, refractory epilepsy has been previously described in ALG1‐CDG (Clayton and Grunewald, ; Dupré et al ., ; Jaeken, ; Freeze et al ., ). All of the 11 ALG1‐CDG patients published so far had “severe”, “multifocal”, “refractory” seizures or presented with an “early epileptic encephalopathy” (Grubenmann et al ., ; Kranz et al ., ; Dupré et al ., ; Fiumara et al , ). EEG was reported as “abnormal” in four children, “multifocal” in one child, and “with electroclinical features of Ohtahara syndrome” in another (Grubenmann et al ., ; Kranz et al ., ; Dupré et al ., ; Fiumara et al , ).…”

“…All of the 11 ALG1‐CDG patients published so far had “severe”, “multifocal”, “refractory” seizures or presented with an “early epileptic encephalopathy” (Grubenmann et al ., ; Kranz et al ., ; Dupré et al ., ; Fiumara et al , ). EEG was reported as “abnormal” in four children, “multifocal” in one child, and “with electroclinical features of Ohtahara syndrome” in another (Grubenmann et al ., ; Kranz et al ., ; Dupré et al ., ; Fiumara et al , ). The presence of epileptic spasms in this population, however, has never been described.…”

“…Similar to ALG1‐CDG, there was no hypsarrhythmia and also very abundant interictal posterior anomalies. The majority of the 54 ALG6‐CDG patients published so far (Haeuptle and Hennet, ; Ishikawa et al ., ; Dercksen et al ., ; Fiumara et al , ; Jaeken et al ., ) also had early‐onset epilepsy. However, few publications describe seizures types and EEG tracings.…”

“…CDG disorders are considered as one of the underlying aetiologies for early‐onset epilepsy and inborn errors of metabolism (Wolf et al ., ; Bahi‐Buisson et al ., ; Fois, ; Noh et al ., ; Rahman et al ., ; Fiumara et al ., ). However, detailed characterization of seizure semiology and neurophysiological patterns is rare.…”