Autoimmune encephalitis is the most commonly identified cause of new-onset refractory status epilepticus, but half remain cryptogenic. Outcome at discharge is poor but improves during follow-up. Epilepsy develops in most cases. The role of anesthetics and immune therapies warrants further investigation.

GABAA receptors (GABARs) mediate the majority of fast inhibitory neurotransmission in the mammalian brain. Functional GABARs are ligand-gated chloride ion channels composed of five individual subunits. These subunits derive from six identified families, many with multiple subtypes (á1-6, â1-3, ã1-3, ä, å and ð). When expressed in Xenopus oocytes or mammalian cells, different GABAR subunit combinations form receptors with unique pharmacological and biophysical properties (Macdonald & Olsen, 1994). These subunits do not assemble randomly, however, for while áâ subunit combinations readily express in mammalian cells, addition of a ã subunit drives expression of áâã isoforms . The majority of native receptors are believed to be formed by combinations of áâã and áâä subunits (McKernan & Whiting, 1996), although the recently characterized å and ð subunits may substitute for ã or ä subunits in some instances (Hedblom & Kirkness, 1997;Davies et al. 1997). In the rat, the ã2 subtype becomes the dominant ã subunit expressed at later developmental stages, and mRNA and membrane protein for this subtype are expressed in most brain regions. In contrast, the ä subunit is restricted only to a few cell populations in the postnatal rat that include thalamic relay neurons, cerebellar granule neurons and dentate granule neurons of the hippocampus (Laurie et al. 1992a,b;Wisden et al. 1992;Sperk et al. 1997). While the ä subunit has been shown to combine preferentially with the á6 subtype in cerebellar granule neurons (Jones et al. 1997), the GABAR subtypes

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

Citation for final published version:Thomas, Rhys 2017. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Please note: Changes made as a result of publishing processes such as copy-editing, formatting and page numbers may not be reflected in this version. For the definitive version of this publication, please refer to the published source. You are advised to consult the publisher's version if you wish to cite this paper.This version is being made available in accordance with publisher policies. See http://orca.cf.ac.uk/policies.html for usage policies. Copyright and moral rights for publications made available in ORCA are retained by the copyright holders.

Angelman syndrome (AS) is a neurogenetic disorder caused by loss of maternal UBE3A expression or mutation-induced dysfunction of its protein product, the E3 ubiquitin-protein ligase, UBE3A. In humans and rodents, UBE3A/Ube3a transcript is maternally imprinted in several brain regions, but the distribution of native UBE3A/Ube3a1 protein expression has not been comprehensively examined. To address this, we systematically evaluated Ube3a expression in the brain and peripheral tissues of wild-type (WT) and Ube3a maternal knockout mice (AS mice). Immunoblot and immunohistochemical analyses revealed a marked loss of Ube3a protein in hippocampus, hypothalamus, olfactory bulb, cerebral cortex, striatum, thalamus, midbrain, and cerebellum in AS mice relative to WT littermates. Also, Ube3a expression in heart and liver of AS mice showed greater than the predicted 50% reduction relative to WT mice. Co-localization 1 Throughout the manuscript, following the standard nomenclature, UBE3A and UBE3A will denote the human gene and protein name, respectively, and Ube3a and Ube3a the rodent gene and protein name, respectively. As indicated here, UBE3A and Ube3a are synonymous with E6-AP.