Mutations in the KCNQ2 and KCNQ3 genes encoding for K v 7.2 (KCNQ2; Q2) and K v 7.3 (KCNQ3; Q3) voltage-dependent K + channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy." In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large Additional Supporting Information may be found in the online version of this article. deletions. One substitution was found in KCNQ3.Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.

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Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array-comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.

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There is growing evidence that brain networks are altered in epileptic subjects. In this study, we investigated the functional connectivity and brain network properties of benign childhood epilepsy with centrotemporal spikes using graph theory. Benign childhood epilepsy with centrotemporal spikes is the most common form of idiopathic epilepsy in young children under the age of 16 years. High-density EEG data were recorded from patients and controls in resting state with eyes closed. Data were preprocessed and spike and spike-free segments were selected for analysis. Phase locking value was calculated for all paired combinations of channels and for five frequency bands (δ, θ, α, β1 and β2). We computed the degree and small-world parameters—clustering coefficient (C) and path length (L)—and compared the two patient conditions to controls. A higher degree at epileptic zones during interictal epileptic spikes (IES) was observed in all frequency bands. Both patient conditions reduced connection at the occipital and right frontal regions close to the epileptic zone in the α band. The “small-world” features (high C and short L) were deviated in patients compared to controls. A changed from an ordered network in the δ band to a more randomly organized network in the α band was observed in patients compared to healthy controls. These findings show that the benign epileptic brain network is disrupted not only at the epileptic zone, but also in other brain regions especially frontal regions.