Developmental epileptic encephalopathy in DLG4‐related synaptopathy

Abstract

AbstractObjectiveThe postsynaptic density protein of excitatory neurons PSD‐95 is encoded by DLG4, de novo pathogenic variants of which lead to DLG4‐related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4‐related synaptopathy.MethodsWe included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep EEG and/or video‐polygraphy and brain MRI were collected. Anti‐seizure medication response was retrospectively assessed by the referring clinician.ResultsA large variety of seizure types was reported, though focal seizures were the most common. Encephalopathy related to status epilepticus during slow sleep (ESES)/developmental epileptic encephalopathy with spike‐wave activation during sleep (DEE‐SWAS) was diagnosed in more than 25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE‐SWAS, as well as some who did not. We could not identify a clear genotype‐phenotype relationship even between individuals with the same DLG4 variants.SignificanceOur study shows that a subgroup of individuals with DLG4‐related synaptopathy has DEE, and around one fourth of them have ESES/DEE‐SWAS. Our study confirms DEE as part of the DLG4‐related phenotypic spectrum. Occurrence of ESES/DEE‐SWAS in DLG4‐related synaptopathy requires to be properly investigated with sleep EEG.