Developmental and epileptic encephalopathy due to SZT2 genomic variants: Emerging features of a syndromic condition

Seizure threshold 2 (SZT2) gene mutations have been associated with developmental and epileptic encephalopathies (DEEs). Following a literature review, we collected 22 patients and identified the main clinical features related to SZT2 variants that are epilepsy with onset within the first years of life, intellectual disability (ID), macrocephaly with dysmorphic facial features, corpus callosum (CC) shape abnormalities, and cortical migration disorders. Moreover, we identified the c.7825T>G homozygous missense variant in SZT2 in two female siblings presenting with focal seizures, mild-moderate ID, behavioral disturbances, and facial dysmorphisms. Interictal Electroencephalogram (EEG) and ictal EEG were both informative and revealed, respectively, temporal bilateral asynchronous slow and epileptiform abnormalities and a focal onset in both of them. Neuroimaging study revealed a thick and abnormally shaped CC. Seizure threshold 2 has been identified as a component of the KICSTOR complex, a newly recognized protein complex involved in the mammalian target of rapamycin (mTOR) pathway. mTOR signaling dysregulation represents common pathogenetic mechanisms that can explain the presence of both epileptogenesis and ID. Even if few cases had been reported, a new clinical phenotype is emerging, and recent hypothesis of hyperactivation of mTORC1 signaling might also open to targeted treatments, challenging an early diagnosis as of paramount importance.