De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

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Recently, mutations in the tau gene on chromosome 17 were found causative for autosomal dominantly inherited frontotemporal dementia and parkinsonism (FTDP‐17). We describe a family carrying a missense mutation at nucleotide 1137 C → T, resulting in the amino acid substitution P301S. Methods of investigations include clinical, electrophysiological, and imaging techniques. This kindred presents with a novel phenotype characterized by an early onset of rapidly progressive frontotemporal dementia and parkinsonism in combination with epileptic seizures. We define the dopaminergic deficits as being predominantly presynaptic by the use of single‐photon emission computed tomography with a dopamine transporter ligand. The association of this early‐onset phenotype with P301S mutation is not entirely consistent with current criteria for the diagnosis of frontotemporal dementias and may encourage the search for tau mutations in diseases similar but not identical to FTDP‐17. Also, the change from proline to serine suggests that this mutation might contribute to tau hyperphosphorylation.

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Background:KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyse the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.Methods:Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results:We identified novel KCNC2 variants in 18 patients with various forms of epilepsy including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy (EOAE), focal epilepsy (FE), and myoclonic-atonic epilepsy (MAE). 10/18 variants were de novo and 8/18 variants were classified as modifying variants. 8 drug responsive cases became seizure-free using valproic acid as monotherapy or in combination including severe DEE cases. Functional analysis of four variants demonstrated gain-of-function in three severely affected DEE cases and loss-of-function in one case with a milder phenotype (GGE) as the underlying pathomechanisms.Conclusion:These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.