Novel SZT2 mutations in three patients with developmental and epileptic encephalopathies

Abstract

Background The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that lowers seizure threshold and may also enhance epileptogenesis. In this study, three patients diagnosed with SZT2‐related developmental and epileptic encephalopathies (DEEs) were reviewed aiming to expand knowledge of the genotype and phenotype of SZT2 mutations. Methods Targeted next‐generation sequencing was performed to identify pathogenic mutations in 205 cases with DEEs of unknown etiology. Detailed clinical and genetic data were collected from SZT2‐associated patients. Results Four novel mutations were found (c.1626 + 1G>A, c.5772dupA, c.4209C > A, c.7307_7308insG) in three patients. All the variants were inherited from their parents. Two patients were siblings and harbored the same mutations and presented developmental delay prior to the onset of seizures. All the individuals were diagnosed as DEEs, drug refractory epilepsy, and experienced status epilepticus (SE); one patient died of SE. One subject showed subependymal nodules as similar as those of tuberous sclerosis complex (TSC) in cranial magnetic resonance imaging (MRI). Conclusion Our results expand the genotype and phenotypes of SZT2‐related DEEs, suggesting that SZT2 mutations play a role in developmental delay and epileptic encephalopathy, with high susceptibility to SE and relatively specific MRI findings.

A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant

“…It was initially suggested that SZT2 variants are associated with two distinctive MRI findings consisting of a thick and shortened corpus callosum (CC) along with a persistent cavum septum pellucidum (CSP) 2 . Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules 6,12,13 . Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them.…”

“…2 Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules. 6,12,13 Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them. Interestingly, the detected CSP might not represent an incidental finding since it was reported to be a developmental anomaly that may contribute to epileptogenesis.…”

“…It was recently shown that SZT2 dysfunction leads to a hyperactivation of the mTORC1 signaling pathway resulting in increased cell proliferation, disturbed connectivity of the brain and epileptogenesis 1,8,9 . SZT2 gene variants are associated with differing phenotypic expressions ranging from mild‐moderate intellectual disabilities without seizures, 10 to an early‐onset epileptic encephalopathy with severe cognitive impairment 6 . The severity of clinical manifestations varies according to the extent of residual protein function.…”

“…6,13 Focal or multifocal epileptiform discharges were seen on the interictal EEG 6,13 while the ictal findings, described in only two previous cases originated from the temporal area. 6 We are the first to report that EIMFS can be secondary to a STZ2 variant. This condition, first described in 1995, 14 is a severe form of pharmacoresistant epilepsy characterized by recurrent seizures with an onset in the first 6 months of life, EEG documentation of seizures with multifocal ictal origins, and migration from one cortical region to another, in addition to profound developmental regression.…”

“…Most were sporadic with only four families affected accounting for 9 of the 21 cases. [4][5][6] We are reporting a new possible familial case, the second of an Arabic descent, 5 harboring a SZT2 gene variant.…”