Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.

The title compound (4) was synthesized, and its crystalline structure was determined. The molecule has C 3 v point symmetry and crystallizes in the trigonal space group R3m. Crystal data for 4:  a = 16.6710(13) Å, b = 16.6710(13) Å, c = 4.2590(3) Å, α = β = 90°, γ = 120°, Z = 3, R(F) = 0.0234. The material has a permanent polarization and consequent pyroelectric properties. The room temperature pyroelectric coefficient was found to be −3 ± 2 μC m-2 K-1, which is in accordance with a calculated value of −3.2 μC m-2 K-1. The molecular dipole moment was determined to be 3.3 ± 0.2 D, the direction of which was unambiguously assigned with respect to the molecular coordinates. The thermal expansivity was determined at temperatures in the range −93 to 200 °C. The relative dielectric permittivity tensor was obtained at optical frequencies (ε11 and ε22 = 3.16 and ε33 = 2.48) and in the microwave region at 35 GHz (ε11 and ε22 = 5.2 ± 0.6 and ε33 = 2.9 ± 0.2), and at low frequencies (120 Hz and 1 kHz), the isotropic permittivity was determined (ε120  Hz = 4.7 ± 0.8 and ε1  kHz = 4.7 ± 1.1). Finally, an estimate of the molecular heat capacity was calculated (C p = 900 J Kg-1 K-1) and the material was considered for potential use in infrared detection as its detectivity merit factor, M r, was determined (M r = 8.8 × 10-2 m2 C-1).

SUMMARYThe first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.

ObjectiveCeramides are precursors of complex sphingolipids (SLs), which are important for normal functioning of both the developing and mature brain. Altered SL levels have been associated with many neurodegenerative disorders, including epilepsy, although few direct links have been identified between genes involved in SL metabolism and epilepsy.MethodsWe used quantitative real-time PCR, Western blotting, and enzymatic assays to determine the mRNA, protein, and activity levels of ceramide synthase 2 (CERS2) in fiibroblasts isolated from parental control subjects and from a patient diagnosed with progressive myoclonic epilepsy (PME). Mass spectrometry and fluorescence microscopy were used to examine the effects of reduced CERS2 activity on cellular lipid composition and plasma membrane functions.ResultsWe identify a novel 27 kb heterozygous deletion including the CERS2 gene in a proband diagnosed with PME. Compared to parental controls, levels of CERS2 mRNA, protein, and activity were reduced by ˜50% in fibroblasts isolated from this proband, resulting in significantly reduced levels of ceramides and sphingomyelins containing the very long-chain fatty acids C24:0 and C26:0. The change in SL composition was also reflected in a reduction in cholera toxin B immunofluorescence, indicating that membrane composition and function are altered.InterpretationWe propose that reduced levels of CERS2, and consequently diminished levels of ceramides and SLs containing very long-chain fatty acids, lead to development of PME.

Third-order optical nonlinear properties of four thienyleneethynylenes and two thienylenevinylenes containing from two to five thiophene units were measured. Third-order nonlinear susceptibilities x (~) ( -3w;o,o,o) at the fundamental wavelength of 1064 nm were measured by third harmonic generation (THG) for thin films of the oligomers in poly(methy1 methacrylate) (PMMA) using the Maker fringe technique. The data were reduced to the equivalent molecular second hyperpolarizabilities y ( -3w;w,o,w). Theoretical calculations of the static (zero-frequency) ( y ) values were performed at the semiempirical Austin model one/finite field (AM1/ FF) and intermediate neglect of differential overlap/single and double configuration interaction (INDO/SDCI) sum-over-states (SOS) levels and at the nonempirical valence effective Hamiltonian (VEH)-SOS level. The evolution of y as a function of the torsion angle between the thiophene rings was investigated via the AM1/ FF method. With the INDO-SOS technique, the frequency dependence of y( -3o;o,o,w) was also analyzed. For the ethynylenes, the experimental THG values of y lie between 63 x and 2300 x esu and increase with the number of heterocycle units of the oligomers. These values are affected by three-photon resonance. The resonant THG y-values of the ethynylenes lie within 10% of the corresponding values of the vinylenes. After a simple correction for three-photon resonance, the dependence of y-values on the number of n-electrons is fitted to power laws and compared with the theoretical calculations. The theoretical static y-values indicate a higher response in the vinylene derivatives than in the corresponding ethynylene derivatives. However, the experimental THG results provide the reverse trend: this can be explained by a stronger resonance enhancement of the THG y-values in the ethynylene compounds, as is demonstrated by the results of the frequency-dependent calculations.

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A series of new sulfur heteroarenes, isoelectronic with dibenzo[g,p]chrysene, have been prepared by double photocyclization of the corresponding tetraaryl substituted ethenes. The first step proceeds efficiently in each case, and the corresponding intermediate sulfur heteroarenes, isoelectronic with phenanthrene, have been isolated. The second ring closure is only efficient when one of the participating aryl substituents is thienyl, which thus manifests a higher electron density on the carbon atom involved in the excited singlet state reaction. Most of the new compounds are of minimal solubility in common solvents and do not display improved electron donor properties otherwise commonly found among heteroaromatics.