Co-occurring malformations of cortical development and SCN1A gene mutations

Objective: To report on six patients with SCN1A mutations and malformations of cortical development (MCDs) and describe their clinical course, genetic findings, and electrographic, imaging, and neuropathologic features.

Methods: Through our database of epileptic encephalopathies, we identified 120 patients with SCN1A mutations, of which 4 had magnetic resonance imaging (MRI) evidence of MCDs. We collected two further similar observations through the European Task-force for Epilepsy Surgery in Children.

Results: The study group consisted of five males and one female (mean age 7.4 ± 5.3 years). All patients exhibited electroclinical features consistent with the Dravet syndrome spectrum, cognitive impairment, and autistic features. Sequencing analysis of the SCN1A gene detected two missense, two truncating, and two splice-site mutations. Brain MRI revealed bilateral periventricular nodular heterotopia (PNH) in two patients and focal cortical dysplasia (FCD) in three, and disclosed no macroscopic abnormality in one. In the MRI-negative patient, neuropathologic study of the whole brain performed after sudden unexpected death in epilepsy (SUDEP), revealed multifocal micronodular dysplasia in the left temporal lobe. Two patients with FCD underwent epilepsy surgery. Neuropathology revealed FCD type IA and type IIA. Their seizure outcome was unfavorable. All four patients with FCD exhibited multiple seizure types, which always included complex partial seizures, the area of onset of which co-localized with the region of structural abnormality.

Significance: MCDs and SCN1A gene mutations can co-occur. Although epidemiology does not support a causative role for SCN1A mutations, loss or impaired protein function combined with the effect of susceptibility factors and genetic modifiers of the phenotypic expression of SCN1A mutations might play a role. MCDs, particularly FCD, can influence the electroclinical phenotype in patients with SCN1A-related epilepsy. In patients with MCDs and a history of polymorphic seizures precipitated by fever, SCN1A gene testing should be performed before discussing any epilepsy surgery option, due to the possible implications for outcome.