ABSTRACTBackgroundMyotonia congenita (MC) is a common channelopathy affecting skeletal muscle and which is due to pathogenic variants within the CLCN1 gene. Various alterations in the function of the channel have been reported and we here illustrate a novel one.MethodsA patient presenting the symptoms of myotonia congenita was shown to bear a new heterozygous missense variant in exon 9 of the CLCN1 gene (c.1010 T > G, p.(Phe337Cys)). Confocal imaging and patch clamp recordings of transiently transfected HEK293 cells were used to functionally analyze the effect of this variant on channel properties.ResultsConfocal imaging showed that the F337C mutant incorporated as well as the WT channel into the plasma membrane. However, in patch clamp, we observed a smaller conductance for F337C at −80 mV. We also found a marked reduction of the fast gating component in the mutant channels, as well as an overall reduced voltage dependence.ConclusionTo our knowledge, this is the first report of a mixed alteration in the biophysical properties of hClC‐1 consisting of a reduced conductance at resting potential and an almost abolished voltage dependence.

Obesity is a serious health problem with tremendous economic and social consequences, which is associated with metabolic diseases and cancer. Currently available anti-obesity drugs acting in the gastrointestinal tract, or the central nervous system have shown limited efficacy in the reduction of obesity, accompanied by severe side effects. Therefore, a novel therapeutic delivery targeting adipocytes and normalizing excess fat transport and accumulation is necessary to maximize efficacy and reduce side effects for long-term treatment. Fatty acid binding protein 4 (FABP4) is an adipokine that coordinates lipid transport in mature adipocyte and its inhibition in obesity model showed weight loss and normalized insulin response. Reduction of FABP4 level in adipocytes was compensated by fatty acid binding protein 5 (FABP5), which resulted in reduction of recovery of obesity and co-morbidities related to obesity by FABP4 knock-down alone. In this study, we developed a non-viral gene delivery system, sh (FABP4/5)/ATS9R, that silences FABP4 and FABP5 simultaneously with oligopeptide (ATS9R) that can selectively target mature adipocyte. For future clinical application to increase patient compliance, sh (FABP4/5)/ATS9R was administered subcutaneously and intraperitoneally to obese animal model and both routes demonstrated startling dual gene efficacy in visceral adipose tissues. Furthermore, dual gene silencing efficiently alleviated obesity, improved insulin sensitivity and restored hepatic metabolism in high fat diet-induced type 2 diabetes mouse model. Targeted-dual gene silencing of sh (FABP4/5)/ATS9R in adipose tissues demonstrated synergistic effects to overcome obesity and obesity-induced metabolic diseases and beneficial effects against liraglutide, providing a great potential for future translational research.

We describe a patient presenting the symptoms of myotonia congenita with a new heterozygous missense variant in exon 9 of the CLCN1 gene (c.1010T>G, p.(Phe337Cys)). The mutation is located in the large extracellular loop between the I and J transmembrane segments of CLCN1 and we functionally analyzed its consequences on channel properties. Confocal imaging showed that the F337C mutant incorporated as well as the WT channel into the plasma membrane. Using patch clamp recordings of WT and F337C hClC-1 channels expressed in HEK293 cells, we observed a smaller conductance for the latter at -80 mV. Using classical voltage protocols and curve fitting procedures, we also found a marked reduction of the fast gating component in the mutant channels, as well as an overall reduced voltage-dependence. The mutation did not alter the pharmacology of the channels. Thus the loss of function is due to a reduction of the opening at resting potential and an inability to quickly activate during the action potential and protect the myocytes against repetitive discharges. To our knowledge, this is the first report of a mixed alteration in the biophysical properties of hClC-1 consisting of a reduced conductance at resting potential and an almost abolished voltage dependence.

Juvenile myoclonic epilepsy (JME), a lifelong disorder that starts during adolescence, is the most common of genetic generalized epilepsy syndromes. JME is characterized by awakening myoclonic jerks and myoclonic-tonic-clonic (m-t-c) grand mal convulsions. Unfortunately, one third of JME patients have drug refractory m-t-c convulsions and these recur in 70–80% who attempt to stop antiepileptic drugs (AEDs). Behavioral studies documented impulsivity, but also impairment of executive functions relying on organization and feedback, which points to prefrontal lobe dysfunction. Quantitative voxel-based morphometry (VBM) revealed abnormalities of gray matter (GM) volumes in cortical (frontal and parietal) and subcortical structures (thalamus, putamen, and hippocampus). Proton magnetic resonance spectroscopy (MRS) found evidence of dysfunction of thalamic neurons. White matter (WM) integrity was disrupted in corpus callosum and frontal WM tracts. Magnetic resonance imaging (MRI) further unveiled anomalies in both GM and WM structures that were already present at the time of seizure onset. Aberrant growth trajectories of brain development occurred during the first 2 years of JME diagnosis. Because of genetic origin, disease causing variants were sought, first by positional cloning, and most recently, by next generation sequencing. To date, only six genes harboring pathogenic variants (GABRA1, GABRD, EFHC1, BRD2, CASR, and ICK) with Mendelian and complex inheritance and covering a limited proportion of the world population, are considered as major susceptibility alleles for JME. Evidence on the cellular role, developmental and cell-type expression profiles of these six diverse JME genes, point to their pathogenic variants driving the first steps of brain development when cell division, expansion, axial, and tangential migration of progenitor cells (including interneuron cortical progenitors) sculpture subtle alterations in brain networks and microcircuits during development. These alterations may explain “microdysgenesis” neuropathology, impulsivity, executive dysfunctions, EEG polyspike waves, and awakening m-t-c convulsions observed in JME patients.

The building of the brain is a multistep process that requires the coordinate expression of thousands of genes and an intense nucleocytoplasmic transport of RNA and proteins. This transport is mediated by karyopherins that comprise importins and exportins. Here, we investigated the role of the ß-importin, importin-8 (IPO8) during mouse cerebral corticogenesis as several of its cargoes have been shown to be essential during this process. First, we showed that Ipo8 mRNA is expressed in mouse brain at various embryonic ages with a clear signal in the sub-ventricular/ventricular zone (SVZ/VZ), the cerebral cortical plate (CP) and the ganglionic eminences. We found that acute knockdown of IPO8 in cortical progenitors reduced both their proliferation and cell cycle exit leading to the increase in apical progenitor pool without influencing the number of basal progenitors (BPs). Projection neurons ultimately reached their appropriate cerebral cortical layer, but their dendritogenesis was specifically affected, resulting in neurons with reduced dendrite complexity. IPO8 knockdown also slowed the migration of cortical interneurons. Together, our data demonstrate that IPO8 contribute to the coordination of several critical steps of cerebral cortex development. These results suggest that the impairment of IPO8 function might be associated with some diseases of neuronal migration defects.

PURPOSE:EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. METHODS:We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/- KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. RESULTS:Nine variants were classified as "pathogenic," 14 as "likely pathogenic," 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. CONCLUSIONS:NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and "microdysgenesis" neuropathology of JME.Genet Med 19 2, 144-156.

New genetic investigation techniques, including next-generation sequencing, epigenetic profiling, cell lineage mapping, targeted genetic manipulation of specific neuronal cell types, stem cell reprogramming, and optogenetic manipulations within epileptic networks are progressively unraveling the mysteries of epileptogenesis and ictogenesis. These techniques have opened new avenues to discover the molecular basis of epileptogenesis and to study the physiologic effects of mutations in epilepsy-associated genes on a multilayer level, from cells to circuits. This manuscript reviews recently published applications of these new genetic technologies in the study of epilepsy, as well as work presented by the authors at the genetic session of the XII Workshop on the Neurobiology of Epilepsy (WONOEP 2013) in Quebec, Canada. Next-generation sequencing is providing investigators with an unbiased means to assess the molecular causes of sporadic forms of epilepsy and has revealed the complexity and genetic heterogeneity of sporadic epilepsy disorders. To assess the functional impact of mutations in these newly identified genes on specific neuronal cell types during brain development, new modeling strategies in animals, including conditional genetics in mice and in utero knock-down approaches, are enabling functional validation with exquisite cell-type and temporal specificity. In addition, optogenetics, using cell-type-specific Cre recombinase driver lines, is enabling investigators to dissect networks involved in epilepsy. In addition, genetically encoded cell-type labeling is providing new means to assess the role of the nonneuronal components of epileptic networks such as glial cells. Furthermore, beyond its role in revealing coding variants involved in epileptogenesis, next-generation sequencing can be used to assess the epigenetic modifications that lead to sustained network hyperexcitability in epilepsy, including methylation changes in gene promoters and noncoding ribonucleic acid (RNA) involved in modifying gene expression following seizures. In addition, genetically based bioluminescent reporters are providing new opportunities to assess neuronal activity and neurotransmitter levels both in vitro and in vivo in the context of epilepsy. Finally, genetically rederived neurons generated from patient induced pluripotent stem cells and genetically modified zebrafish have become high-throughput means to investigate disease mechanisms and potential new therapies. Genetics has changed the field of epilepsy research considerably, and is paving the way for better diagnosis and therapies for patients with epilepsy.

Chronic food restriction (FR) and maintenance of low body weight have long been known to increase the rewarding and motor-activating effects of addictive drugs. However, the neurobiological mechanisms through which FR potentiates drug reward remain largely unknown. Melanin-concentrating hormone (MCH) signaling could be one of these mechanisms since this peptide is involved in energy homeostasis and Modulates mesolimbic dopaminergic transmission. The purpose of the present study was to test this hypothesis by investigating the impact of FR on amphetamine reward in wild-type (WT) and knockout-mice lacking the melanin-concentrating hormone receptor-1 (MCHR1-KO). The rewarding effects of amphetamine (0.75-2.25 mg/kg, i.p.) were measured with the conditioned place preference (CPP) technique. The food of the mice was restricted to maintain their body weight at 80-85% of their free-feeding (FF) weight throughout the entire CPP experiment. Locomotor activity of the animals was recorded during the conditioning sessions. Our results show that locomotion of all the food-restricted mice treated with saline or amphetamine increased over the sessions whatever the genotype. On the place preference test, the amplitude of CPP induced by 0.75 mg/kg amphetamine was higher in food restricted WT mice than in free-fed WT mice and food restricted MCHR1-KO mice. However, FR did not affect amphetamine reward in MCHR1-KO mice. The present results indicate that MCH signaling could be involved in the ability of FR to increase amphetamine-induced CPP. (C) 2014 Elsevier B.V. All rights reserved.

Heterozygous mutations in Myoclonin1/EFHC1 co-segregate with juvenile myoclonic epilepsy (JME) phenotypes. In adolescent patients with JME, they produce subtle malformations of cortical and subcortical architecture whereas homozygous F229L mutation in infancy induces severe brain pathology and death. However, the underlying pathological mechanisms for these observations remain unknown. We first demonstrated that EFHC1 is a microtubule-associated protein (MAP) involved in cell division and radial migration during cerebral corticogenesis. Next, we showed that JME mutations, including F229L, act in a dominant-negative manner to impair mitotic spindle organization. We also found that overexpression of EFHC1 mutants forms disrupted radial and tangential migration by affecting morphology of radial glia and migrating neurons. These results show how Myoclonin1/EFHC1 mutations disrupt brain development and could potentially produce structural brain abnormalities on which epileptogenesis is established.

Background Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene have been identified in patients with benign (familial) infantile convulsions (B(F)IC), infantile convulsions with choreoathetosis (ICCA) and paroxysmal dyskinesias (PDs). However it remains unknown whether PRRT2 mutations are causal in other epilepsy syndromes. After we discovered a PRRT2 mutation in a large family with ICCA containing one individual with febrile seizures (FS) and one individual with West syndrome, we analysed PRRT2 in a heterogeneous cohort of patients with different types of infantile epilepsy. Methods We screened a cohort of 460 patients with B(F)IC or ICCA, fever related seizures or infantile epileptic encephalopathies. All patients were tested for point mutations using direct sequencing. Results We identified heterozygous mutations in 16 individuals: 10 familial and 6 sporadic cases. All patients were diagnosed with B(F)IC, ICCA or PD. We were not able to detect mutations in any of the other epilepsy syndromes. Several mutation carriers had learning disabilities and/or impaired fine motor skills later in life. Conclusions PRRT2 mutations do not seem to be involved in the aetiology of FS or infantile epileptic encephalopathies. Therefore B(F)IC, ICCA and PD remain the core phenotypes associated with PRRT2 mutations. The presence of learning disabilities or neuropsychiatric problems in several mutation carriers calls for additional clinical studies addressing this developmental aspect in more detail.

Juvenile Myoclonic Epilepsy (JME) accounts for almost 12% of all epilepsies and is one of the most frequent forms of genetic generalized epilepsies. Genetic studies have revealed that mutations in EFHC1 (EF-hand containing one) account for 3 to 9% of all cases around the world. This gene encodes a protein that is not an ion channel, and several studies have tried to find its cellular role. In this article, we review the various functions that have been proposed for this protein. Interestingly, all of them could affect brain development at different steps, suggesting that the developmental assembly of neural circuits may play a prominent role in JME.

In the course of our investigations on Umutambasha in order to identify its convulsant principles, small quantities of monofluoroacetate were observed in stem bark, leaves, and fruits of this plant newly identified as Dichapetalum michelsonii Hauman. Conclusive evidence for a monofluoroacetate presence came from its isolation from the freeze-dried extract of stem bark. Three free unusual amino acids, named N-methyl-α-alanine, N-methyl-β-alanine, and 2,7-diaminooctan-1,8-dioic acid, described for the first time in a plant, and known trigonelline were also isolated from the stem bark of D. michelsonii. Structure elucidations were mainly achieved by spectroscopic methods (1H-NMR, 2D-NMR, MS) and by comparison with authentic references. These unusual amino acids were detected by a fast, reliable TLC analysis in all our batches of Umutambasha, suggesting that they could be used for identification purposes in case of human or livestock intoxications. Finally, EEG recordings and behavioural observations performed in mice suggested that the convulsive patterns produced by Umutambasha are the consequence of monofluoroacetate presence in D. michelsonii.

An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

This chapter presents recent works on Myocloni1/ EFHC1 a protein encoded by an epilepsy causing gene of juvenile myoclonic epilepsy (JME), one of the most frequent forms of idiopathic or genetic generalized epilepsies. Myoclonin 1/EFHC1 is a microtubule-associated protein involved in the regulation of cell division. In vitro, EFHC1 loss of function disrupted mitotic spindle organization, impaired M phase progression, induced microtubule bundling and increased apoptosis. EFHC1 impairment in the rat developing neocortex by ex vivo and in utero electroporation caused a marked disruption of radial migration. This effect was a result of cortical progenitors failing to exit the cell cycle. On the other hand, defects in the radial glia scaffold organization and in the locomotion of postmitotic neurons. Mutant analysis of Defhc1 lossand gain-of-function alleles in vivo in Drosophila revealed a number of neuronal defects, including abnormal synaptic development characterized by extensive satellite bouton formation, increased frequency of spontaneous neurotransmitter release, and aberrations in dendritic arbour morphogenesis. Thus, Myoclonin 1/ EFHC1 is a regulator of cell division and neuronal migration during cortical development synaptic bouton and dendritic morphogenesis. Disruption of these properties lead to JME, being now therefore considered as a developmental disease. Juvenile myoclonic epilepsy (JME) is the most frequent form of idiopathic/genetic generalized epilepsy. It accounts for 2–12 % of all epilepsies. JME symptoms of myoclonias and tonicclonic convulsions appear in adolescence in an otherwise normal person with normal neurological and cognitive functions (Delgado-Escueta and Bacsal, 1984)1. Five percent of these patients, five percent of their affected family members and eight percent of a 252 patient Corresponding author : Prof Thierry GRISAR, MD,PhD, University of Liège, GIGA Neuroscience Blvd de l’Hopital 1, 4000 Liège BELGIUM e-mail : tgrisar@ulg.ac.be. Japer's Basic M ecanism s of he Eppsies Japer's Basic M ecanism s of he Eppsies cohort followed for over 20 years only have seizures when triggered by external factors such as alcohol use, fatigue, menstruation and sleep deprivation. To understand the disease mechanisms underlying the stages of susceptibility and epileptogenesis in JME, many have tried to define its complex heritability and identify the genes corresponding to the fifteen chromosomal loci so far linked to the disease2 (see also chapter ...in this book). In 2004, Suzuki et al. identified several heterozygous missense mutations in a gene called EFHC1 3 in different unrelated families with JME probands. Since then, heterozygous non sense, deletion frame shifts and novel missense mutations have been identified in various populations of Italy, Austria and Chile 4–7 .Nine percent of sporadic JME cases detected in families consecutively seen in epilepsy clinics of Mexico and Honduras and 3 % of clinic patients from Japan carry mutations in EFHC1. This represents the highest number and percentage of mutations found for a juvenile myoclonic epilepsy causing gene of any population group 7. The gene encodes a 75-kDa protein with three DM10 domains of unknown function and a single EF-hand motif, a Ca2+-binding domain. The transcript is observed in many cell type of human tissue including brain (in particular in ependymal or periventricular cells) but also best expressed in dividing cells with highest levels in lung and testis 3. It was first proposed that EFHC1 was “pro-apoptotic” when overexpression in hippocampal neurons in vitro induced apoptotic cell death. This effect was significantly reduced by any of the five mutations associated with JME. Patch-clamp analysis of BHK (Baby Hamster Kidney) cells transfected with Cav2.3 VDCC (voltage-dependent calcium channel) and EFHC1 showed significantly increased R-type Ca2+ currents. So, the pro-apoptotic effect of EFHC1 was assigned to this enhancing effect on Ca2+ through Cav2.3 VDCC 3. In 2005, another research group pointed out that EFHC1 is orthologous to Rib72, an axonemal protein of Chlamydomonas reinhardtii. They demonstrated that EFHC1 is abundantly expressed in mouse tissues that have motile cilia or flagella, including the brain, and suggested that it plays a role in the intrinsic properties of these organelles 8. One of our laboratories previously reported that the subcellular distribution of EFHC1 in different cell lines varied during the cell cycle. In interphase cells, the protein is present in the cytoplasm and nucleus, except nucleoli and is particularly concentrated at the centrosome. During mitosis, EFHC1 is localized at spindle poles of the mitotic spindle and also at the midbody during cytokinesis 9. These results suggest that EFHC1 could play an important role during cell division and in particular during brain development since mRNA expression is higher at embryonic stages as compared to adult 10. More recently, we demonstrated that EFHC1 is a microtubule-associated protein (MAP) playing a key role in neuronal migration 11. In this chapter we review these putative roles of Myoclonin 1 / EFHC1 or during brain development and during adulthood. We posit an hypothesis that JME is a developmental disease involving neuronal migration and synaptic bouton and dendritic morphogenesis. EFHC1/MYOCLONIN1, A PROTEIN OF UNKNOWN FUNCTION Myoclonin 1 /EFHC1 gene is located on chromosome 6 (6p11–12) between markers D6S1960 and D6S11024, spans 72 kb and contains 11 exons. This gene encodes a protein of 640 amino acids. A domain search identified three tandemly repeated so called DM10 domains, a motif with unknown function. This protein also contains a single EF-hand, a well known Ca2+binding motif, from which it was named EFHC1 for EF-hand Containing 1 (Figure 1). This motif is located at the C-terminus between amino acid 578 and 606 and encoded by a nucleotide sequence present in exon 10. Page 2 Myoclonin1/EFHC1 in cell division, neuroblast migration, synapse/dendrite formation in juvenile myoclonic epilepsy Japer's Basic M ecanism s of he Eppsies Japer's Basic M ecanism s of he Eppsies Figure 1. Schematic representation of the EFHC1/Myoclonin1 gene, the long and short forms of the EFHC1 protein and the different mutations found co segregated with the JME phenotype The transcript undergo alternative splicing in exon 4, resulting in a C-terminally truncated protein, eliminating the EF-hand domain and two DM10 sequences. This last short form therefore only contains 278 amino acids, the first 240 being common with the entire molecule.

The epilepsies affect around 50 million people worldwide and constitute in 2012 the second neurological group of diseases. Anyone can suffer one type of epilepsy with more or less severe repeated seizures independently of age, race, or of socioeconomic or geographic situation. In Europe, the prevalence of epilepsy is of 8.2 per 1,000 corresponding to 6 million individuals with active epilepsy and around 15 million having experienced epilepsy during their lives (see [1]). Since almost two or even three decades now, the epileptologists repeatedly claim that in spite of the scientific progress in the field of basic neurosciences on the one hand and in clinical and neuropharmacological research on the other hand, 30–40 % of their patients remain incurable or at least drug-resistant. It took a long time to recognize the extreme diversity of the epileptic syndromes and to remain concentrated on the treatment of the seizures themselves. One of the symptoms of this is the ongoing use of the term ‘‘Epilepsy’’ in the singular form. For years, this attitude was clearly justified, since the antiepileptic drugs were efficient in at least half of the patients. Therefore, from the clinical point of view, considerable efforts have been developed to better identify and classify new epileptic syndromes and sometimes diseases. Truly, the principal symptom that links the different epileptic diseases is the seizure itself, a phenomenon due to the sudden occurrence in a particular area of the cerebral cortex of an epileptogenic circuit probably starting by hypersynchronous bioelectrical discharges in a set of cortical neurons then propagating in specific parts of the brain through synaptic connections. Therefore, for years, the therapeutic efforts tended to limit excitation and/or to favour inhibition considering epilepsy (i.e. ‘‘in singular’’) as a clear imbalance between these two phenomena. Although several experimental evidences illustrated that one can produce huge epileptogenic circuits by favouring GABAergic inhibitory inputs in some circumstances, one has to observe that this ‘‘old thought’’ is still hard to tackle among the clinical and also the pharmacological world. Since 1995, positional cloning strategies in multigenerational families with autosomal dominant transmission have revealed several genes (KCNQ2, KCNQ3, CHRNA4, CHRNA2, CHRNB2, SCN1B, SCN1A, SCN2A, GABRG2, GABRA1...) and numerous loci for febrile seizures and epilepsies. Most of these genes encode neuronal ion channel or neurotransmitter receptor subunits creating a first enthusiastic hypothesis that at least idiopathic generalized epilepsies could be considered as a new group of channelopathies. However, molecular approaches have revealed great genetic heterogeneity, with most genes remaining to be identified. One of the major challenges is now to understand phenotype–genotype correlations. Following these advances, it became more and more popular to think of the antiepileptic treatment in terms of their basic mechanisms of action, i.e. acting on Na or K channels or GABA transmission, etc...., as if a specific and precise molecular mechanism of action in given epileptic syndromes (childhood absence epilepsy, medial temporal lobe epilepsy, or the Dravet syndrome, etc....) were completely elucidated. We have to admit that this probably still constitutes an illusion. Today, the effort to clarify the effectiveness of a rationale of antiepileptic treatment on a (somewhat empirical) clinical basis and multidisciplinary T. Grisar (&) CHU, Department of Neurology, GIGA Neurosciences Research Centre, University of Liege, Liege, Belgium e-mail: tgrisar@ulg.ac.be

Heterozygous mutations in Myoclonin1/EFHC1 cause juvenile myoclonic epilepsy (JME), the most common form of genetic generalized epilepsies, while homozygous F229L mutation is associated with primary intractable epilepsy in infancy. Heterozygous mutations in adolescent JME patients produce subtle malformations of cortical and subcortical architecture, whereas homozygous F229L mutation in infancy induces severe brain pathology and death. However, the underlying pathological mechanisms for these observations remain unknown. We had previously demonstrated that EFHC1 is a microtubule-associated protein (MAP) involved in cell division and radial migration during cerebral corticogenesis. Here, we show that JME mutations, including F229L, do not alter the ability of EFHC1 to colocalize with the centrosome and the mitotic spindle, but act in a dominant-negative manner to impair mitotic spindle organization. We also found that mutants EFHC1 expression disrupted radial and tangential migration by affecting the morphology of radial glia and migrating neurons. These results show how Myoclonin1/EFHC1 mutations disrupt brain development and potentially produce structural brain abnormalities on which epileptogenesis is established.

BACKGROUND:Given the continuous knowledge progression and the growing number of available antiepileptic drugs (AEDs), making appropriate treatment choices for patients with epilepsy is increasingly difficult. While published guidelines help for separate clinical aspects, patients with a combination of specific characteristics may escape proper guidance. This study aimed to determine the appropriateness of AEDs for particular clinical variables and to offer treatment recommendations for adult patients with epilepsy in a user-friendly format for practicing neurologists.METHODS:Using the RAND/UCLA Appropriateness Method, the appropriateness of AEDs as initial/second mono-therapy and combination therapy was assessed in relation to selected clinical variables by a Belgian panel of 13 experts in epilepsy. Panel recommendations for particular patient profiles were determined by the outcome of these separate ratings.RESULTS:The appropriateness outcome of individual AEDs was not substantially different between first and second mono-therapy; valproate was considered appropriate for all types of generalised and partial seizures. The outcome for combination therapy was highly dependent on the type of AED and seizures. With respect to co-morbidities and co-treatments, levetiracetam and pregabalin proved to have the least contra-indications. For the elderly and with respect to factors related to the female reproductive system the appropriateness of AEDs showed a more diffuse pattern. Although caution was deemed necessary for some combinations, the AEDs were never considered inappropriate regarding their drug interaction profile.CONCLUSIONS:The Epi-Scope(®) tool that displays appropriateness recommendations for highly specific, possibly complex cases, supports optimal treatment choices for adult patients with epilepsy in daily practice.

The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis, anxiety, and sleep regulation. Since the MCH receptor-1 (MCH-R1), the only functional receptor that mediates MCH functions in rodents, facilitates behavioral performance in hippocampus-dependent learning tasks, we investigated whether glutamatergic transmission in CA1 pyramidal cells could be modulated in mice lacking the MCH-R1 gene (MCH-R1(-/-)). We found that both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated transmissions were diminished in the mutant mice compared with their controls. This deficit was explained, at least in part, by a postsynaptic down-regulation of these receptors since the amplitude of miniature excitatory postsynaptic currents and the NMDA/AMPA ratio were decreased. Long-term synaptic potentiation (LTP) was also impaired in MCH-R1(-/-) mice. This was due to an altered induction, rather than an impaired, expression because repeating the induction stimulus restored LTP to a normal magnitude. In addition, long-term synaptic depression was strongly diminished in MCH-R1(-/-) mice. These results suggest that MCH exerts a facilitatory effect on CA1 glutamatergic synaptic transmission and long-term synaptic plasticity. Recently, it has been shown that MCH neurons fire exclusively during sleep and mainly during rapid eye movement sleep. Thus these findings provide a mechanism by which sleep might facilitate memory consolidation.