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ObjectiveSomatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD.MethodsWe identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD.ResultsWe observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen.InterpretationWe report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

Abstract Background Upon cellular entry retroviruses must avoid innate restriction factors produced by the host cell. For human immunodeficiency virus (HIV) human restriction factors, APOBEC3 (apolipoprotein-B-mRNA-editing-enzyme), p21 and tetherin are well characterised. Results To identify intrinsic resistance factors to HIV-1 replication we screened 19,121 human genes and identified 114 factors with significant inhibition of infection. Those with a known function are involved in a broad spectrum of cellular processes including receptor signalling, vesicle trafficking, transcription, apoptosis, cross-nuclear membrane transport, meiosis, DNA damage repair, ubiquitination and RNA processing. We focused on the PAF1 complex which has been previously implicated in gene transcription, cell cycle control and mRNA surveillance. Knockdown of all members of the PAF1 family of proteins enhanced HIV-1 reverse transcription and integration of provirus. Over-expression of PAF1 in host cells renders them refractory to HIV-1. Simian Immunodeficiency Viruses and HIV-2 are also restricted in PAF1 expressing cells. PAF1 is expressed in primary monocytes, macrophages and T-lymphocytes and we demonstrate strong activity in MonoMac1, a monocyte cell line. Conclusions We propose that the PAF1c establishes an anti-viral state to prevent infection by incoming retroviruses. This previously unrecognised mechanism of restriction could have implications for invasion of cells by any pathogen.

Nocturnal frontal-lobe epilepsy is characterized by paroxysmal arousals, motor seizures with dystonic or hyperkinetic features, and episodic nocturnal wanderings. Carbamazepine is effective for seizure control in some of these patients, but seizures may be refractory to multiple antiepileptic drugs. We report on eight children between ages 4-16 years with nocturnal frontal-lobe epilepsy who had a dramatic response to oxcarbazepine at standard recommended doses, some of whom were refractory to previous antiepileptic medications. Brain magnetic resonance imaging, routine electroencephalogram, and prolonged, continuous video-electroencephalogram telemetry were performed in all children. Nocturnal frontal-lobe epilepsy was diagnosed by demonstrating ictal electroencephalogram changes originating from the frontal lobes. The children were followed for response of seizures to oxcarbazepine, side effects, and routine blood tests, including serum 10-monohydroxide derivative levels. The mean oxcarbazepine dose was 30.4 mg/kg/day ± 11.7 (mean ± SD); the mean 10-monohydroxide level was 23.1 μg/mL ± 8.6 (mean ± SD). Seizures improved within 4 days of oxcarbazepine initiation in six children, whereas two children required higher doses. Their follow-up has ranged from 12 to 24 months, without seizure recurrence or serious side effects. Our patients demonstrate the efficacy of oxcarbazepine for nocturnal hyperkinetic seizures in children with nocturnal frontal-lobe epilepsy. [Copyright &y& Elsevier]